Carbapenem compounds

ABSTRACT

A compound or its pharmaceutically acceptable salt represented by the following formula: 
                         
The invention is a carbapenem compound which has a potent antibacterial activity over a broad range of Gram negative and Gram positive bacteria, especially penicillin-resistant  Streptococcus pneumoniae  (PRSP) which has been isolated at an elevated frequency in recent years and thus causes a serious clinical problem, and  Haemophilus influenzae  which has acquired resistance against the existing β-lactam antibiotics over a wide scope due to penicillin-binding protein (PBP) mutations such as β-lactamase non-producing ampicillin-resistant (BLNAR)  Haemophilus influenzae , and has excellent oral absorbability.

This application is a U.S. national stage of International ApplicationNo. PCT/JP02/11477 filed Nov. 1, 2002.

TECHNICAL FIELD

The present invention relates to a new carbapenem compound. In moredetail, the present invention relates to a carbapenem compound, whereina substituted phenyl or a substituted thienyl is directly substituted atposition 3 of 7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a basicnucleus of the carbapenem compound. Furthermore, the present inventionrelates to an antibacterial agent containing such a compound.

BACKGROUND ART

The carbapenem compounds which have been developed and commercializedare poor in absorbability from the digestive tract and therefore, theyare clinically used only in a form of injection, mainly intravenousinjection. However, in the clinical field, it is desirable to selectseveral administration routes from the viewpoint of circumstances orwishes of a patient, a therapeutic object, etc. Especially, oraladministration of an antibacterial agent is easy and convenient foradministration to a patient in comparison with injection. In view of thecare of a patient at home, oral administration of the antibacterialagent is more convenient and the clinical usability is extremely high.It has been strongly desired in the clinical field to develop acarbapenem compound which has a potent antibacterial activity especiallyagainst penicillin-resistant Streptococcus pneumoniae (PRSP) which hasbeen isolated at an elevated frequency in recent years and thus causes aserious clinical problem, and Haemophilus influenzae which has acquiredresistance against the existing β-lactam antibiotics over a wide scopedue to penicillin-binding protein (PBP) mutations such as β-lactamasenon-producing ampicillin-resistant (BLNAR) Haemophilus influenzae, andis rich in safety and is orally administrable. However none of suchagents has been put on the market. Tricyclic carbapenem compounds whichhave been studied and developed until now are disclosed for example, inWO92/03437. These compounds have a characteristic structure in a sidechain having a ring which is fused via C—C bond and they are modified toa prodrug thereof for increase of oral absorbability, but their safetyin the clinical test is not reported. Besides, there are several known1β methylcarbapenem compounds (Japanese patent publication 2-49783,Japanese patent publication 8-53453, Japanese patent publication4-279588, Japanese patent publication 2-223587, WO98/34936, WO99/57121,Antimicrobial Agents and Chemotherapy, Mar. 1999, p460–464). All of themhave a structural property having 1β-methyl group and a side chain viasulfide bond which are the said to contribute to an increase of chemicalstability and in vivo (biological) stability, and are modified to aprodrug of them for increase of oral absorbability. Especially, theclinical trial was carried out on compounds disclosed in Japanese patentpublication 2-49783 and Japanese patent publication 8-53453, but thesafety of them and so on have been not clear.

On the other hand, carbapenem compounds having an aryl ring via C—C bondas a side chain structure were known since 1980s (U.S. Pat. No.4,775,669, U.S. Pat. No. 5,258,509, Tetrahedron, 1983, Vol. 39,p2531–2549, Journal of Medicinal Chemistry, 1987, Vol. 30, p871–880).Although there are many other reports on these compounds, these reportsare concerned only to studies and developments on injections thereof,but not to studies for oral application thereof.

DISCLOSURE OF INVENTION

The object of the present invention is to provide a carbapenem compoundwhich has a potent antibacterial activity over a broad range of Grampositive bacteria and Gram negative bacteria, especially againstpenicillin-resistant Streptococcus pneumoniae (PRSP) which has beenisolated at an elevated frequency in recent years and thus causes aserious clinical problem, and Haemophilus influenzae which has acquiredresistance against the existing β-lactam antibiotics over a wide scopedue to penicillin-binding protein (PBP) mutations such as β-lactamasenon-producing ampicillin-resistant (BLNAR) Haemophilus influenzae, andhas excellent oral absorbability.

The present inventors have intensively studied to find that thecarbapenem compound, wherein a substituted phenyl or a substitutedthienyl is directly substituted at position 3 of7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a basic nucleus of thecarbapenem compound has a potent antibacterial activity over a broadrange of Gram positive bacteria and Gram negative bacteria, especiallyagainst penicillin-resistant Streptococcus pneumoniae (PRSP) which hasbeen isolated at an elevated frequency in recent years and thus causes aserious clinical problem, and Haemophilus influenzae which has acquiredresistance against the existing β-lactam antibiotics over a wide scopedue to penicillin-binding protein (PBP) mutations such as β-lactamasenon-producing ampicillin-resistant (BLNAR) Haemophilus influenzae.Further, they have also found that a compound having a group substitutedonto the 2-carboxyl group, the said group being capable of regeneratinga carboxyl group by hydrolyzing in the living body, shows a goodabsorbability from the digestive tract by oral administration, and showsa potent antibacterial activity after converted into a 2-de-esterifiedcompound in the living body, and further shows an excellent resistanceto renal dehydropeptidase, and finally have accomplished the presentinvention.

Namely, the present invention relates to:

1. The carbapenem compound represented by a following formula [1],

wherein ring E is benzene or thiophen.

-   R¹ is C₁ to C₃ alkyl or C₁ to C₃ alkyl substituted by hydroxy.-   A is —(CH₂)_(r)—, wherein r is 1 to 3; —(CH₂)_(s)—O—(CH₂)_(t)—,    wherein s and t are respectively independently 0 to 3;    —(CH₂)_(s)—S—(CH₂)_(t)—, wherein s and t are the same as defined    above; —(CH₂)_(s)—NR^(a)—(CH₂)_(t)—, wherein s and t are the same as    defined above, and R^(a) is hydrogen atom or optionally substituted    C₁ to C₆ alkyl; —(CH₂)_(s)—NR^(a)—CR^(b)═N—(CH₂)_(t)—, wherein    R^(a), s and t are the same as defined above, and R^(b) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(s)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(t)—, wherein R^(a),    R^(b), s and t are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl.-   R⁰ is hydrogen atom or a following formula [2],

wherein X is oxygen atom or sulfur atom, R² and R³ are respectivelyindependently (1) hydrogen atom, (2) optionally substituted C₁ to C₆alkyl, (3) optionally substituted C₃ to C₇ cycloalkyl, (4) optionallysubstituted aryl which may optionally contain heteroatom(s) therein, (5)optionally substituted aralkyl in which ring may optionally containheteroatom(s), or (6) optionally substituted 3 to 7 membered heteroring; or R² and R³ are combined together with the N atom to form a 3 to7 hetero ring which may be optionally substituted, or R⁰ is a followingformula [3],

wherein X is oxygen atom or sulfur atom, m is 0 or 1, R^(3a) is hydrogenatom, optionally substituted C₁ to C₆ alkyl, optionally substituted C₃to C₇ cycloalkyl, optionally substituted aryl which may optionallycontain heteroatom(s) therein, optionally substituted aralkyl in whichring may optionally contain heteroatom(s), or optionally substituted 3to 7 membered hetero ring; but when X is oxygen atom and m is 1, R^(3a)may be further a group which regenerates a carboxyl group by hydrolysisin vivo, but R^(3a) is other group except hydrogen atom when t is 0, andm is 1,

-   R is hydrogen atom or a group which regenerates a carboxyl group by    hydrolysis in vivo.-   Y is hydrogen atom, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, optionally    protected hydroxy group, C₁ to C₆ alkyloxy, C₁ to C₆ alkylthio, C₂    to C₇ alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy, C₂ to C₇    alkyloxycarbonyl, optionally protected carboxyl, halogen atom,    cyano, —NR⁴R⁵, —OCONR⁴R⁵, —CONR⁴SO₂R⁵, —SO₂ NR⁴R⁵, —NR⁴SO₂NR⁴R⁵ or    —NR⁴CONR⁴R⁵, or C₁ to C₆ alkyl substituted by a group selected from    a group of optionally protected hydroxy group, C₁ to C₆ alkyloxy, C₁    to C₆ alkylthio, C₂ to C₇ alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy,    C₂ to C₇ alkyloxycarbonyl, optionally protected carboxyl, a halogen    atom, cyano, —NR⁴R⁵, —CONR⁴R⁵, —OCONR⁴R⁵, —CONR⁴SO₂R⁵, —SO₂NR⁴R⁵,    —NR⁴SO₂NR⁴R⁵ and —NR⁴CONR⁴R⁵. Amino group may be optionally    protected and plural Ys may be substituted on ring E.-   R⁴ and R⁵ are respectively independently (1) hydrogen atom, (2)    optionally substituted C₁ to C₆ alkyl, (3) optionally substituted C₃    to C₇ cycloalkyl, (4) optionally substituted aryl which may    optionally contain heteroatom(s) therein, (5) optionally substituted    aralkyl in which ring may optionally contain heteroatom(s), or (6)    optionally substituted 3 to 7 membered hetero ring; or R⁴ and R⁵ are    combined together with the N atom to form pyrrolidine, piperidine or    azepane,    or its pharmaceutically acceptable salt.-   2. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 1, wherein a group which regenerates a    carboxyl group by hydrolysis in vivo is represented by a following    formula [4],

wherein R⁶ is hydrogen atom or C₁ to C₆ alkyl, R⁷ is optionallysubstituted C₁ to C₆ alkyl, optionally substituted C₃ to C₇ cycloalkyland n is 0 or 1.

-   3. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 1, wherein R is represented by a following    formula [4],

wherein R⁶, R⁷ and n are the same as defined in the above 2.

-   4. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 1, wherein R is pivaloyloxymethyl group.-   5. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 1, wherein, R is hydrogen atom.-   6. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 5, wherein R¹ is    1-hydroxyethyl group.-   7. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is hydrogen    atom.-   8. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is represented    by a following formula [2],

wherein X, R² and R³ are the same as defined in above 1.

-   9. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is represented    by a following formula [2a],

wherein R² and R³ are the same as defined in the above 1.

-   10. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is represented    by a following formula [3],

wherein X, m and R^(3a) are the same as defined in the above 1.

-   11. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is represented    by a following formula [3a],

wherein m and R^(3a) are the same as defined in the above 1.

-   12. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 1 to 6, wherein R⁰ is represented    by a following formula [3b],

wherein R′ is a group which regenerates a carboxyl group by hydrolysisin vivo.

-   13. The carbapenem compound represented by a following formula [1d],

wherein ring E is benzene or thiophen.

-   A is —(CH₂)_(r)—, wherein r is 1 to 3; —(CH₂)_(s)—O—(CH₂)_(t)—,    wherein s and t are respectively independently 0 to 3;    —(CH₂)_(s)—S—(CH₂)_(t)—, wherein s and t are the same as defined    above; —(CH₂)_(s)—NR^(a)—(CH₂)_(t)—, wherein s and t are the same as    defined above, and R^(a) is hydrogen atom or optionally substituted    C₁ to C₆ alkyl; —(CH₂)_(s)—NR^(a)—CR^(b)═N—(CH₂)_(t)—, wherein    R^(a), s and t are the same as defined above, and R^(b) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(s)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(t)—, wherein R^(a),    R^(b), s and t are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alky,-   R⁰ is hydrogen atom or a following formula [2],

wherein X is oxygen atom or sulfur atom, R² and R³ are respectivelyindependently (1) hydrogen atom, (2) optionally substituted C₁ to C₆alkyl, (3) optionally substituted C₃ to C₇ cycloalkyl, (4) optionallysubstituted aryl which may optionally contain heteroatom(s) therein, (5)optionally substituted aralkyl in which ring may optionally containheteroatom(s), or (6) optionally substituted 3 to 7 membered heteroring; or R² and R³ are combined together with the N atom to form a 3 to7 hetero ring which may be optionally substituted, or else R⁰ isrepresented by a following formula [3],

wherein X is oxygen atom or sulfur atom, m is 0 or 1, R^(3a) is hydrogenatom, optionally substituted C₁ to C₆ alkyl, optionally substituted C₃to C₇ cycloalkyl, optionally substituted aryl which may optionallycontain heteroatom(s) therein, optionally substituted aralkyl in whichring may optionally contain heteroatom(s), or optionally substituted 3to 7 membered hetero ring; but when X is oxygen atom and m is 1, R^(3a)may be further a group which regenerates a carboxyl group by hydrolysisin vivo, but R^(3a) is other group except hydrogen atom when t is 0, andm is 1,

-   R is hydrogen atom or a group which regenerates a carboxyl group by    hydrolysis in vivo.-   Y is hydrogen atom, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, optionally    protected hydroxy group, C₁ to C₆ alkyloxy, C₁ to C₆ alkylthio, C₂    to C₇ alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy, C₂ to C₇    alkyloxycarbonyl, optionally protected carboxyl, a halogen atom,    cyano, —NR⁴R⁵, —OCONR⁴R⁵, —CONR⁴SO₂R⁵, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁴R⁵ or    —NR⁴CONR⁴R⁵, or, C₁ to C₆ alkyl substituted by a group selected from    a group of optionally protected hydroxy group, C₁ to C₆ alkyloxy, C₁    to C₆ alkylthio, C₂ to C₇ alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy,    C₂ to C₇ alkyloxycarbonyl, optionally protected carboxyl, a halogen    atom, cyano, —NR⁴R⁵, —CONR⁴R⁵, —OCONR⁴R⁵, —CONR⁴SO₂R⁵, —SO₂NR⁴R⁵,    —NR⁴SO₂NR⁴R⁵ and —NR⁴CONR⁴R⁵. Amino group may be optionally    protected and plural Ys may substitute on ring E.-   R⁴ and R⁵ are respectively independently (1) hydrogen atom, (2)    optionally substituted C₁ to C₆ alkyl, (3) optionally substituted C₃    to C₇ cycloalkyl, (4) optionally substituted aryl which may    optionally contain heteroatom(s) therein, (5) optionally substituted    aralkyl in which ring may contain heteroatom(s) or (6) optionally    substituted 3 to 7 membered hetero ring; or R⁴ and R⁵ are combined    together with the N atom to form pyrrolidine, piperidine or azepan,    or its pharmaceutically acceptable salt.-   14. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is hydrogen atom.-   15. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is represented by a following    formula [2],

wherein X, R² and R³ are the same as defined in the above 13.

-   16. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is represented by a following    formula [2a],

wherein X, R² and R³ are the same as defined in the above 13.

-   17. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is represented by a following    formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13.

-   18. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is represented by a following    formula [3a],

wherein m and R^(3a) are the same as defined in the above 13.

-   19. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein R⁰ is represented by a following    formula [3b],

wherein R′ is the same as defined in the above 12.

-   20. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 13 to 19, wherein R is hydrogen    atom.-   21. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene and R⁰ is    hydrogen atom.-   22. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene and R⁰ is    represented by a following formula [2],

wherein X, R² and R³ are the same as defined in the above 13.

-   23. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene and R⁰ is    represented by a following formula [2a],

wherein R² and R³ are the same as defined in the above 13.

-   24. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene and R⁰ is    represented by a following formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13.

-   25. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene and R⁰ is    represented by a following formula [3a],

wherein m and R^(3a) are the same as defined in the above 13.

-   26. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein E is benzene and R⁰ is    represented by a following formula [3b],

wherein R′ is the same as defined in the above 12.

-   27. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 21 to 26, wherein R is hydrogen    atom.-   28. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3; —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above; —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl; —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl, and R⁰ is hydrogen    atom.-   29. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3; —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above; —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl; —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl, and R⁰ is a group    represented by a following formula[2],

wherein X, R² and R³ are the same as defined in the above 13.

-   30. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3; —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above; —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl; —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl, and R⁰ is a group    represented by a following formula [2a],

wherein R² and R³ are the same as defined in the above 13.

-   31. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3; —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above; —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl; —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alky, and R⁰ is a group    represented by a following formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13.

-   32. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3; —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above; —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl; —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alkyl;    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alky, and R⁰ is a group    represented by a following formula [3a],

wherein m and R^(3a) are the same as defined in above 13.

-   33. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is    —(CH₂)_(v)—O—(CH₂)_(w)—, wherein one of v and w is 0 and the other    is 0 to 3, —(CH₂)_(v)—S—(CH₂)_(w)—, wherein v and w are the same as    defined above, —(CH₂)_(v)—NR^(a)—(CH₂)_(w)—, wherein v and w are the    same as defined above, and R^(a) is hydrogen atom or optionally    substituted C₁ to C₆ alkyl, —(CH₂)_(v)—NR^(a)—CR^(b)═N—(CH₂)_(w)—,    wherein R^(a), v and w are the same as defined above, and R^(b) is    hydrogen atom or optionally substituted C₁ to C₆ alky,    —(CH₂)_(v)—NR^(a)—C(—NR^(b)R^(c))═N—(CH₂)_(w)—, wherein R^(a),    R^(b), v and w are the same as defined above, and R^(c) is hydrogen    atom or optionally substituted C₁ to C₆ alkyl, and R⁰ is a group    represented by a following formula [3b],

wherein R′ is the same as defined in the above 12.

-   34. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 28 to 33, wherein R is hydrogen    atom. 35. The carbapenem compound or its pharmaceutically acceptable    salt according to the above 13, wherein ring E is benzene, A is    —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and    R⁰ is hydrogen atom.-   36. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and R⁰ is a    group represented by a following formula [2],

wherein X, R² and R³ are the same as defined in the above 13.

-   37. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and R⁰ is a    group represented by a following formula [2a],

wherein R² and R³ are the same as defined in the above 13.

-   38. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and R⁰ is a    group represented by a following formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13.

-   39. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and R⁰ is a    group represented by a following formula [3a],

wherein m and R^(3a) are the same as defined in the above 13.

-   40. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, and a group R⁰    is a group represented by a following formula [3b],

wherein R′ is the same as defined in the above 12.

-   41. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 35 to 40, wherein R is hydrogen    atom.-   42. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is hydrogen atom.-   43. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is a group represented by a following    formula [2],

wherein X, R² and R³ are the same as defined in the above 13.

-   44. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is a group represented by a following    formula [2a],

wherein R² and R³ are the same as defined in the above 13.

-   45. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is a group represented by a following    formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13.

-   46. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is a group represented by a following    formula [3a],

wherein m and R^(3a) are the same as defined in the above 13.

-   47. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl and R⁰ is a group represented by a following    formula [3b],

wherein R′ is the same as defined in the above 12.

-   48. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, R⁰ is hydrogen atom, Y is hydrogen atom and the    the said A is bound to the benzene ring at meta or para position    against the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is    bound to the benzene.-   49. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, Y is hydrogen atom and R⁰ is a group represented    by a following formula [2],

wherein X, R² and R³ are the same as defined in the above 13, and thesaid A is bound to the benzene ring at meta or para position against theposition where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to thebenzene.

-   50. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, Y is hydrogen atom and R⁰ is a group represented    by a following formula[2a],

wherein R² and R³ are the same as defined in the above 13, and the saidA is bound to the benzene ring at meta or para position against theposition where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to thebenzene.

-   51. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, Y is hydrogen atom and R⁰ is a group represented    by a following formula [3],

wherein X, m and R^(3a) are the same as defined in the above 13, and thesaid A is bound to the benzene ring at meta or para position against theposition where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to thebenzene.

-   52. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, Y is hydrogen atom and a group R⁰ is a group    represented by a following formula [3a],

wherein m and R^(3a) are the same as defined in the above 13, and thesaid A is bound to the benzene ring at meta or para position against theposition where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to thebenzene.

-   53. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R is    pivaloyloxymethyl, Y is hydrogen atom and R⁰ is a group represented    by a following formula [3b],

wherein R′ is the same as defined in the above 12, and the said A isbound to the benzene ring at meta or para position against the positionwhere 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.

-   54. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH—or —NH—, R⁰ is CONH₂,    and the said A is bound to the benzene ring at meta or para position    against the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is    bound to the benzene.-   55. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH—or —NH—, R⁰ is CONHMe,    and the said A is bound to the benzene ring at meta or para position    against the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is    bound to the benzene.-   56. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, A is —(CH₂)₂—,    —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONMe₂,    and the said A is bound to the benzene ring at meta or para position    against the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is    bound to the benzene.-   57. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 54 to 56, wherein Y is hydrogen    atom.-   58. The carbapenem compound or its pharmaceutically acceptable salt    according to any one of the above 54 to 57, wherein R is hydrogen    atom.-   59. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONH₂, and the said A is bound to    the benzene ring at meta or para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   60. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONHMe, and the said A is bound to    the benzene ring at meta or para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   61. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONMe₂, and the said A is bound to    the benzene ring at meta or para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   62. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONH₂, Y is hydrogen atom and the    said A is bound to the benzene ring at meta or para position against    the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to    the benzene.-   63. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, or —CH₂—, R⁰ is CONH₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   64. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —OCH₂—, —CH₂O—, or —O—, R⁰ is CONH₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   65. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONH₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   66. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONHMe, Y is hydrogen atom and the    said A is bound to the benzene ring at meta or para position against    the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to    the benzene.-   67. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, or —CH₂—, R⁰ is CONHMe, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   68. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —OCH₂—, —CH₂O—, —O—, R⁰ is CONHMe, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   69. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONHMe, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   70. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—,    —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONMe₂, Y is hydrogen atom and the    said A is bound to the benzene ring at meta or para position against    the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to    the benzene.-   71. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —(CH₂)₂—, or —CH₂—, R⁰ is CONMe₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   72. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —OCH₂—, —CH₂O—, —O—, R⁰ is CONMe₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   73. The carbapenem compound or its pharmaceutically acceptable salt    according to the above 13, wherein ring E is benzene, R is    pivaloyloxymethyl, A is —NHCH₂—, —CH₂NH— or —NH—, R⁰ is CONMe₂, Y is    hydrogen atom and the said A is bound to the benzene ring at meta or    para position against the position where    7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene.-   74. A medicament, which comprises the carbapenem compound or its    pharmaceutically acceptable salt according to any one of the above 1    to 73 as an active ingredient.-   75. An antibacterial agent containing the carbapenem compound or its    pharmaceutically acceptable salt according to any one of the above 1    to 73 as an active ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION

The first aspect of the present invention relates to the abovecarbapenem compounds. Various terms and preferable examples referred tothe present specification are explained as follows.

“C₁ to C₃ alkyl” in R¹ includes a straight or branched chain C₁ to C₃alkyl, such as methyl, ethyl, n-propyl, isopropyl, etc., preferablyethyl or isopropyl.

“C₁ to C₃ alkyl substituted by hydroxy” in R¹ includes a group having C₁to C₃, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxy-1-methylethyl, 1-hydroxypropyl, preferably 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, etc., and more preferably,1-hydroxyethyl.

“C₁ to C₆ alkyl” includes a straight or branched chain C₁ to C₆ alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, etc., preferably a straight or branchedchain C₁ to C₃ alkyl, such as methyl, ethyl, n-propyl, isopropyl, etc.,and more preferably methyl or ethyl.

“Aryl which may optionally contain heteroatom(s) therein” includes a 5to 10 membered mono cyclic or fused polycyclic aromatic ring containing0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, suchas phenyl, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,indolyl, benzothiazolyl, naphthyl, quinazolyl, isoquinazolyl, etc.,preferably pyridyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl,and more preferably pyridyl, thienyl, furyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl or thiazolyl.

“Aralkyl in which ring may optionally contain heteroatom(s) therein”includes a combination of a 5 to 10 membered mono cyclic or fusedpolycyclic aromatic ring containing 0 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur atoms with C₁ to C₃ alkylene, such asbenzyl, phenethyl, pyridylmethyl, pyrimidylmethyl, pyridazinylmethyl,thienylmethyl, furylmethyl, pyrrolylmethyl, imidazolylmethyl,oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl,triazolylmethyl, indolylmethyl, benzothiazolylmethyl, naphthylmethyl,quinazolylmethyl, isoquinazolylmethyl, etc., preferably pyridylmethyl,pyrimidylmethyl, pyridazinylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl,thiazolylmethyl, isothiazolylmethyl, or triazolylmethyl, more preferablypyridylmethyl, thienylmethyl, furylmethyl, pyrrolylmethyl,imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl, or thiazolylmethyl.

“C₃ to C₇ cycloalkyl” includes one having C₃ to C₇, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

The substituent of “optionally substituted C₁ to C₆ alkyl”, “optionallysubstituted C₃ to C₇ cycloalkyl”, “optionally substituted aryl which mayoptionally contain heteroatom(s) therein” and “optionally substitutedaralkyl in which a ring may optionally contain heteroatom(s) therein”includes hydroxy group, C₁ to C₆ alkyloxy, C₁ to C₆ alkylthio, C₂ to C₇alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy, C₂ to C₇ alkyloxycarbonyl, C₃to C₇ cycloalkyl, optionally protected carboxyl, a halogen atom, cyano,—NR⁴R⁵, —CONR⁴R⁵, —OCONR⁴R⁵, —CONR⁴SO₂R⁵, —SO₂NR⁴R⁵, —R⁴SO₂NR⁴R⁵,—NR⁴CONR⁴R⁵, (wherein R⁴ and R⁵ are the same as defined above.),—COOCH₂OCOR⁸ (wherein R⁸ is C₁ to C₆ alkyl), etc. These substituents maybe optionally protected by an appropriate protecting group. The positionand the number of the substituent(s) are not limited as long as they arechemically possible.

“C₁ to C₆ alkyloxy” includes a straight or branched chain C₁ to C₆alkyloxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc., preferably astraight or branched chain C₁ to C₃ alkyloxy, such as methoxy, ethoxyn-propoxy, isopropoxy, etc., more preferably methoxy or ethoxy.

“C₁ to C₆ alkylthio” includes a straight or branched chain C₁ to C₆alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, n-hexylthio,etc., preferably a straight or branched chain C₁ to C₃ alkylthio, suchas methylthio, ethylthio n-propylthio, isopropylthio, more preferablymethylthio or ethylthio.

“C₂ to C₇ alkylcarbonyl” includes a straight or branched chain C₂ to C₇alkylcarbonyl, such as acetyl, propionyl, n-propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, etc., preferablya straight or branched chain C₂ to C₄ alkylcarbonyl, such as acetyl,propionyl, n-propylcarbonyl, isopropylcarbonyl, etc., more preferablyacetyl or propionyl.

“C₂ to C₇ alkycarbonyloxy” includes a straight or branched chain C₂ toC₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy,n-hexylcarbonyloxy, etc., preferably a straight or branched chain C₂ toC₄ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, etc., more preferablyacetyloxy or propionyloxy.

“C₂ to C₇ alkyloxycarbonyl” includes a straight or branched chain C₂ toC₇ alkyloxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl,n-hexyloxycarbonyl, etc., preferably a straight or branched chain C₂ toC₄ alkyloxycarbonyl, such as methoxycarbonyl, ethoxycarbonyln-propoxycarbonyl, isopropoxycarbonyl, etc., more preferablymethoxycarbonyl or ethoxycarbonyl.

“A halogen atom” includes fluorine atom, chlorine atom, bromine atom oriodine atom, preferably fluorine atom, chlorine atom, or bromine atom.

Preferable one in R² and R³ is hydrogen atom, optionally substituted C₁to C₆ alkyl, optionally substituted aryl which may optionally containheteroatom(s) therein, or optionally substituted aralkyl in which ringmay optionally contain heteroatom(s) therein, more preferably hydrogenatom, optionally substituted methyl, optionally substituted ethyl, arylwhich may optionally contain heteroatom(s) therein, or aralkyl in whichring may optionally contain heteroatom(s) therein.

“3 to 7 membered hetero ring” in R², R³ and R^(3a) and “3 to 7 memberedhetero ring” in which R² and R³ are combined together with the nitrogenatom to form, includes a 3 to 7 membered saturated or unsaturated heteroring containing 1 to 2 nitrogen atoms, 0 to 1 sulfur atom or 0 to 1oxygen atom, such as aziridine, azetidine, pyrrolidine, dihydropyrrole,piperidine, tetrahydropyridine, piperazine, thiazoline, thiazolidine,morpholine, thiomorpholine, azepan, tetrahydroazepine,tetrahydrodiazepine, hexahydrodiazepine, etc., preferably azetidine,pyrrolidine, tetrahydropyridine, piperazine, thiazoline, thiazolidine,morpholine, or thiomorpholine, more preferably azetidine, pyrrolidine,tetrahydropyridine, thiazoline, thiazolidine, or morpholine.

Preferable group of R^(3a) is hydrogen atom, optionally substituted C₁to C₆ alkyl, optionally substituted aryl which may optionally containheteroatom(s) therein, or optionally substituted aralkyl in which ringmay optionally contain heteroatom(s) therein, more preferably hydrogenatom, optionally substituted methyl, optionally substituted ethyl, arylwhich may optionally contain heteroatom(s) therein, or aralkyl in whichring may optionally contain heteroatom(s) therein.

A substituent on “an optionally substituted C₃ to C₇ hetero ring”includes C₁ to C₆ alkyl, hydroxy, C₁ to C₆ alkyloxy, C₂ to C₇alkylcarbonyl, C₂ to C₇ alkylcarbonyloxy, C₂ to C₇ alkyloxycarbonyl,carboxyl, a halogen atom, cyano, etc.

“A group which regenerates a carboxyl group by hydrolysis in vivo”includes any group as long as the group regenerates a carboxyl group byhydrolysis in vivo, and includes any group which is used for conversioninto a compound called a prodrug, preferably is a group represented by afollowing formula [4],

wherein R⁶, R⁷ and n are the same as defined above.

Examples thereof are pivaloyloxymethyl, acetyloxymethyl,cyclohexylacetyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl,ethoxycarbonyloxy-1-ethyl, cyclohexyloxycarbonyloxy-1-ethyl, etc.,preferably pivaloyloxymethyl. Other group which regenerates a carboxylgroup by hydrolysis in vivo includes C₁ to C₆ alkyl such as methyl,ethyl etc., C₂ to C₁₂ alkyloxyalkyl, such as methoxymethyl,ethoxymethyl, 2-methoxyethyl, 2-methoxyethoxymethyl, etc., and(2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl,(5-tert-butyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl, etc., more preferably(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

Various protecting groups used usually are used as the protecting groupof carboxyl group and include preferably a straight or branched C₁ to C₆alkyl, such as methyl, ethyl, isopropyl, tert-butyl, etc., C₁ to C₆halogenoalkyl, such as 2-iodoethyl, 2,2,2-trichloroethyl, etc., C₂ to C₇alkyloxymethyl, such as methoxymethyl, ethoxymethyl, isobutoxymethyl,etc, C₂ to C₇ alkylcarbonyloxymethyl, such as acetyloxymethyl,propionyloxymethyl, butyriloxymethyl, pivaloyloxymethyl, etc., C₄ to C₁₁1-alkyloxycarbonyloxyethyl, such as 1-ethoxycarbonyloxyethyl, etc.,aralkyl, such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,etc., C₃ to C₇ alkenyl, such as allyl, 3-methylallyl, etc., benzhydryl,phthalidyl, (2-oxo-1,3-dioxol-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-t-butyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl, etc.

Various protecting groups used usually can be used as the protectinggroup of hydroxy, amino, amidino or guanidino group and includepreferably C₂ to C₇ alkyloxycarbonyl, such as tert-butoxycarbonyl, etc,C₁ to C₅ halogenoalkyloxycarbonyl, such as 2-iodoethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc., optionally substituted C₂ to C₇alkenyloxycarbonyl, such as allyloxycarbonyl, etc., aralkyloxycarbonyl,such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc., trialkylsilyl,such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc.Furthermore, various protecting groups which regenerates a hydroxyand/or amino, amidino or guanidino group by hydrolysis in vivo, can beused, such as (5-methyl-1,3-dioxolen-2-on-4-yl)methoxycarbonyl.

Preferable ring E is benzene.

About A, wherein r is 1 to 2, or s and/or t are 0 is preferable. Morepreferable A is —(CH₂)₂—, —CH₂—, —OCH₂—, —CH₂O—, —O—, —NHCH₂—, —CH₂NH—or —NH—.

Preferable X is an oxygen atom.

Preferable Y is a hydrogen atom, an optionally protected hydroxy, a C₁to C₆ alkyloxy, a halogen atom, or a cyano group, more preferably ahydrogen atom.

The pharmaceutically acceptable salt of the carbapenem of the presentinvention includes a conventional non-toxic salt. Such salts include, asa salt with an intramolecular carboxylic acid, a salt with an inorganicbase, such as sodium, potassium, calcium, magnesium, ammonium salt,etc., a salt with an organic base, such as triethylammonium, pyridinium,diisopropylammonium salt, etc., or as a salt with an intramolecularbasic group, a salt with an inorganic acid such as hydrochloric acid,sulfuric acid, phosphoric acid, or a salt with an organic acid, such asformic acid, acetic acid, oxalic acid, methanesulfuric acid,benzenesulfonic acid, etc.

The carbapenem of the present invention or the pharmaceuticallyacceptable salt thereof may be in the form of an anhydride thereof, ahydrate thereof, or a solvate thereof.

The second aspect of the present invention relates to a pharmaceuticalcomposition containing a carbapenem compound as an active ingredient.

Since the carbapenem compound of the present invention has a potentantibacterial activity, excellent oral absorbability and furthermore,has stability to DHP-1, the compound is expected as a potentantibacterial agent which is clinically applicable, especially an orallyantibacterial agent.

The carbapenem compound of the present invention exhibits broadantibacterial spectrum including gram positive bacteria, such asStaphylococcus aureus, Staphylococcus epidermidis, Streptococcuspyogenes, Streptococcus pneumoniae, Enterococcus faecalis, etc., andgram negative bacteria, such as Escherichia coli, the genus Proteus,Klebsiella pneumoniae, Haemophilus influenzae, Neisseria gonorrhoe, thegenus Branhamella, etc. The carbapenem compound of the present inventionhas been found to have a potent antibacterial activity especiallyagainst Haemophilus influenzae (which widely gain resistance to theinhibitory effect of known β-lactam agents together with mutation of apenicillin binding protein (PBP), which have been recently increasinglyisolated and provide a clinical trouble, such as penicillin resistantStreptococcus pneumoniae (PRSP) and β-lactamase non-producing ampicillinresistant Haemophilus influenzae (BLNAR)).

It is well known that dehydropeptidase-I (DHP-I), a renal enzyme caneasily hydrolyze a carbapenem derived from natural sources. Some of thepresent carbapenem compounds show resistance to DHP-I and it is possibleto use them solely. However, it is possible to use the compound of thepresent invention together with a DHP-I inhibitor, if necessary.

When used as an antibacterial agent in the treatment of infectiousdiseases caused by bacteria, the carbapenem compounds of the presentinvention are administered, for example, orally in the form of a tablet,a capsule, powders, syrup, etc., or parenterally such as intravenousinjection, intramuscular injection, or intrarectal administration.

The suitable administration forms as mentioned above may be prepared ina conventional manner by mixing an active ingredient with apharmaceutically acceptable carrier, excipient, binder, stabilizer, etc.When administered in the form of injection, a pharmaceuticallyacceptable buffering agent, a solubilizer, an isotonic agent, etc. maybe added thereto.

The dosage of the compound varies according to the symptoms, ages, bodyweights, the administration form, the frequency of the administration,etc., but it is usually in the range of 100 to 3000 mg per day for anadult, which is administered once or divided into several dosage units.Besides, the dosage of the compound may be increased or decreased, ifnecessary.

The carbapenem compound of the present invention is prepared by variousknown methods (Tetrahedron, 39, 2531–2549 (1983), Tetrahedron Letters,31, 2853–2856 (1990), ibid. 34, 3211–3214 (1993), ibid. 36, 4563–4566(1995), Japanese patent publication B 4-40357, etc.). One of thesemethods, for example is illustrated as follows:

wherein, ring E, R¹, A, R⁶, R⁷ and Y are the same as defined above, R⁹is a protecting group of carboxyl group, R^(1a) and R^(1b) are C₁ to C₃alkyl or C₁ to C₃ alkyl substituted by a protected hydroxy group,respectively, and R^(0a) and R^(0b) are respectively, hydroxy group,amino group, amidino group, guanidino group, a protecting group ofmercapto group, a group represented by a following formula [2],

wherein X, R² and R³ are the same as defined above, or a grouprepresented by a following formula [3],

wherein X, m and R^(3a) are the same as defined above, and Z is chlorineatom, bromine atom or iodine atom.

Step 1: Process for Preparation of Compound 4

Compound 4 is prepared by the reaction of compound 2 and compound 3 inthe presence of acid catalyst in an inactive solvent. The catalystincludes zinc chloride, zinc bromide, zinc iodide, tin(IV) chloride,trifluoromethanesulfonic acid trimethylsilyl ester, borontrifluoride•diethy ether complex, etc.

The inactive solvent includes dichloromethane, 1,2-dichloroethane,acetonitrile, monochlorobenzene, dioxane, tetrahydrofuran, benzene,toluene, etc.

The reaction is carried out at −78 to +60° C., preferably −30 to +40° C.

The starting material 3 is prepared by enol-etherifying variousacetophenone derivatives or acetylthiophene derivatives prepared inaccordance with known methods (e.g. Synthesis and reaction of organiccompound [II] page 751–875 (1977), Sin Jikken Kagaku Kouza edited by TheChemical Society of Japan, Vol. 14 (Maruzen), or Organic Synthesis[III], Aldehyde•Ketone•Quinone, page 149–353 (1991), Sin Jikken KagakuKouza edited by The Chemical Society of Japan, 4th Edition (Maruzen)).

Step 2: Process for Preparation of Compound 6

A corresponding hemiacetal compound is prepared by heating compound 4and compound 5A under dehydrated condition in an inactive solvent. Theinactive solvent includes dichloromethane, 1,2-dichloroethane,monochlorobenzene, benzene, toluene, xylene, etc.

The reaction is carried out at +50 to +200° C., preferably +80 to +150 °C. According to a known method (e.g., Journal of Organic Chemistry, 61,7889–7894 (1996)), compound 4 and compound 5B are reacted in thepresence of a base in an inactive solvent to give an imido compound andthen the imido compound can be reduced to give a correspondinghemiacetal compound. The base includes triethylamine,diisopropylethylamine, N-methylmorpholine, etc. The inactive solventused in imidation includes dichloromethane, 1,2-dichloroethane,monochlorobenzene, etc. The reaction temperature used in imidation is at−50 to +50 ° C., preferably −30 to +30 ° C. The reduction agent ispreferably zinc, and the reduction is carried out preferably in asolvent such as a mixture of acetic acid and dichloromethane, a mixtureof acetic acid and 1,2-dichloroethane, a mixture of acetic acid andmonochlorobenzene, etc. The reaction temperature in reduction is at −50to +50° C., preferably −30 to +30° C.

Thus obtained hemiacetal compound is reacted with a chlorination agent,such as thionyl chloride, oxalyl chloride, phosphorous oxychloride,etc., to give compound 6. The chlorination reaction is carried out inthe presence of a base, such as lutidine, pyridine, quinoline,diisopropylethylamine, triethylamine, etc., in an inactive solvent, suchas ether, tetrahydrofuran, dichloromethane, etc. The reactiontemperature is at −78 to +60° C., preferably −30 to +40° C.

Step 3: Process for Preparation of Compound 7

Compound 6 is reacted with triphenylphosphine in the presence of a base,such as lutidine, pyridine, quinoline, diisopropylethylamine,triethylamine, etc., in an inactive solvent, such as tetrahydrofuran,dioxane, dimethoxyethane, etc., to give compound 7. The reactiontemperature is at 0 to +100° C., preferably +10 to +70° C.

Step 4: Process for Preparation of Compound 8

If necessary, the removal of the protecting groups of hydroxy group inR^(1a) and a protecting group in R^(0a) is carried out, followed byre-protection of them to give compound 8. The removal of the protectinggroup and the introduction of the protecting group are carried out byconventional methods (See e.g., T. W. Greene: Protecting groups inOrganic Synthesis, J. Wiley & Sons Inc., 1981).

Step 5: Process for Preparation of Compound 9

The cyclization reaction of compound 8 is carried out in an inactivesolvent, such as benzene, toluene, xylene, etc., at +80 to +200° C. togive compound 9.

Step 6: Process for Preparation of Compound 10

The protecting group in R^(0b) of compound 9 is removed, if necessaryfollowed by subjecting to a known chemical reaction (acylation,carbamate-formation, urea-formation, etc.) to give compound 10. Theremoval of the protecting group is carried out by conventional methods(See e.g., T. W. Greene: Protecting groups in Organic Synthesis, J.Wiley & Sons Inc., 1981).

Step 7: Process for Preparation of Carbapenem 1 (R=hydrogen Atom)

Carbapenem 1 can be prepared by removing a protecting group of carboxylgroup in R⁹ of compound 9 and when hydroxy group in R^(1b) is protected,by removing the protecting group. The removal of the protecting group iscarried out by conventional methods, namely by treating with an acid, abase, a reduction agent, etc. (See e.g., T. W. Greene: Protecting groupsin Organic Synthesis, J. Wiley & Sons Inc., 1981). Furthermore, whenR^(0b) is a protecting group of hydroxy group, amino group, amidinogroup, guanidino group or mercapto group, a subsequent known chemicalreaction (acylation, carbamate-formation, urea-formation) may be carriedout, if necessary.

Step 8: Process for Preparation of Carbapenem Compound 1 (R=a ProtectingGroup which Regenerates a Carboxyl Group by Hydrolysis in vivo.)

By introducing a protecting group which regenerates a carboxyl group byhydrolysis in vivo into carbapenem compound 1 (R=hydrogen atom) inaccordance with a conventional method, carbapenem compound 1 (R=aprotecting group which regenerates a carboxyl group by hydrolysis invivo.) is obtainable. For example, a cabapenem compound (R=hydrogenatom) or its carboxylic acid salt is reacted and esterified with ahalide 11, if necessary in the presence of a base, such asdiisopropylethylamine, triethylamine, 4-dimethylaminopyridine, potassiumcarbonate or sodium hydrogencarbonate to give a carbapenem compound (R=aprotecting group which regenerates a hydroxy group by hydrolysis invivo).

The reaction solvent is not limited as long as it is an inactivesolvent, and preferably dimethyl formamide, dimethyl sulfoxide,hexamethylphosphoramide, acetonitrile, dioxane, tetrahydrofuran,acetone, etc. The carboxylic acid salt includes preferably sodium saltand potassium salt. The reaction temperature is at −78 to +100° C.,preferably −20 to +60° C. Furthermore, when R^(0b) is a protecting groupof hydroxy group, amino group, amidino group, or mercapto group, asubsequent known chemical reaction (acylation, carbamate-formation,urea-formation) may be carried out, if necessary.

In the above step, when compound 5A or compound 5B, wherein R⁹ is aprotecting group which regenerates a carboxyl group by hydrolysis invivo, is used, and the remaining steps are carried out, carbapenemcompound 1 (R=a protecting group which regenerates carboxyl group byhydrolysis in vivo.) can be directly prepared.

When the above reaction is completed, a reaction product is isolated bya conventional organic procedure, but when a water soluble product isobtained, a solution of the reaction mixture is neutralized, and thesolution is subjected to a column chromatography using absorption resin,etc. and parts which an object compound is eluted are separated andlyophilized to give a reaction product.

The process for preparation of the carbapenem compound is not limited bythe above preparation methods.

The optical isomers based on asymmetric carbon atoms on the presentcarbapenem compound at the 5- and 6-positions of7-oxo-1-azabicyclo[3.2.0]hept-2-ene, a basic nuclear, present as shownin a following formula [1],

These isomers are all conveniently expressed by only one formula, butthe scope of the present invention should not be construed to be limitedthereto, and includes all isomers and a mixture of isomers based on eachasymmetric carbon atom. The preferable isomers are ones wherein the5-carbon atom has an R-configuration such as (5R,6R)-compounds or(5R,6S)-compounds. More preferable compounds are ones represented by afollowing formula [1b],

Furthermore, when R¹ is 1-hydroxyethyl group, there are isomers havingan R-configuration and an S-configuration at the position 8 as shown ina following formula [1c], and an isomer having the R-configuration ispreferable.

In regard to the substitution position of -A-R⁰ on benzene ring orthiophene ring, a side chain at the position 3, the said position is notlimited, and meta or para position is preferable in case of the benzenering.

The carbapenem compound of the present inventions can be illustrated byfollowing examples 1 to 72.

TABLE 1

Com- pound No. R¹ R A 1 CH(OH)CH₃ —CH₂OCOt-Bu

2 CH(OH)CH₃ —CH₂OAc

3 CH(OH)CH₃

4 CH(OH)CH₃

5 CH(OH)CH₃

6 CH(OH)CH₃

7 CH(OH)CH₃ H

8 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 2

Compound No. R¹ R A 9 CH(OH)CH₃ —CH₂OCOt-Bu

10 CH(OH)CH₃ —CH₂OAc

11 CH(OH)CH₃

12 CH(OH)CH₃

13 CH(OH)CH₃

14 CH(OH)CH₃

15 CH(OH)CH —CH₂OCOt-Bu

16 CH(OH)CH₃ H

TABLE 3

Compound No. R¹ R A 17 CH(OH)CH₃ —CH₂OCOt-Bu

18 CH(OH)CH₃ —CH₂OAc

19 CH(OH)CH₃

20 CH(OH)CH₃

21 CH(OH)CH₃

22 CH(OH)CH₃

23 CH(OH)CH₃ H

24 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 4

Compound No. R¹ R A 25 CH(OH)CH3 —CH₂OCOt-Bu

26 CH(OH)CH₃ —CH₂OCOt-Bu

27 CH(OH)CH₃ —CH₂OCOt-Bu

28 CH(OH)CH₃ —CH₂OCOt-Bu

29 CH(OH)CH₃ —CH₂OCOt-Bu

30 CH(OH)CH₃ —CH₂OCOt-Bu

31 CH(OH)CH₃ —CH₂OCOt-Bu

32 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 5

Com- pound No. R¹ R A 33 CH(OH)CH₃ —CH₂OCOt-Bu

34 CH(OH)CH₃ —CH₂OCOt-Bu

35 CH(OH)CH₃ —CH₂OCOt-Bu

36 CH(OH)CH₃ —CH₂OCOt-Bu

37 CH(OH)CH₃ —CH₂OCOt-Bu

38 CH(OH)CH₃ —CH₂OCOt-Bu

39 CH(OH)CH₃ —CH₂OCOt-Bu

40 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 6

Com- pound No. R¹ R A 41 CH(OH)CH₃ —CH₂OCOt-Bu

42 CH(OH)CH₃ —CH₂OCOt-Bu

43 CH(OH)CH₃ —CH₂OCOt-Bu

44 CH(OH)CH₃ —CH₂OCOt-Bu

45 CH(OH)CH₃ —CH₂OCOt-Bu

46 CH(OH)CH₃ —CH₂OCOt-Bu

47 CH(OH)CH₃ —CH₂OCOt-Bu

48 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 7

Compound No. R¹ R A 49 CH(OH)CH₃ —CH₂OCOt-Bu

50 CH(OH)CH₃ —CH₂OCOt-Bu

51 CH(OH)CH₃ —CH₂OCOt-Bu

52 CH(OH)CH₃ —CH₂OCOt-Bu

53 CH(OH)CH₃ —CH₂OCOt-Bu

54 CH(OH)CH₃ —CH₂OCOt-Bu

55 CH(OH)CH₃ —CH₂OCOt-Bu

56 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 8

Com- pound No. R¹ R A 57 CH(OH)CH₃ —CH₂OCOt-Bu

58 CH(OH)CH₃ —CH₂OCOt-Bu

59 CH(OH)CH₃ —CH₂OCOt-Bu

60 CH(OH)CH₃ —CH₂OCOt-Bu

61 CH(OH)CH₃ —CH₂OCOt-Bu

62 CH(OH)CH₃ —CH₂OCOt-Bu

63 CH(OH)CH₃ —CH₂OCOt-Bu

64 CH(OH)CH₃ —CH₂OCOt-Bu

TABLE 9

Com- pound No. R¹ R A 65 CH(OH)CH₃ —CH₂OCOt-Bu

66 CH(OH)CH₃ —CH₂OCOt-Bu

67 CH(OH)CH₃ —CH₂OCOt-Bu

68 CH(OH)CH₃ —CH₂OCOt-Bu

69 CH(OH)CH₃ —CH₂OCOt-Bu

70 CH₂CH₃ —CH₂OCOt-Bu

71 C(OH)(CH₃)₂ —CH₂OCOt-Bu

72 CH(CH₃)₂ —CH₂OCOt-Bu

The compounds illustrated above have stereoisomers as described above orelse stereoisomers based on asymmetric carbon atoms, and the compoundsinclude all these isomers.

EXAMPLE

The present invention is illustrated by following examples, but thepresent invention is not limited by these examples.

The following abbreviations are used in Examples.

-   Me: methyl-   t-Bu: tert-butyl-   Ph: phenyl-   Ac: acetyl-   Boc: tert-butoxycarbonyl-   ALOC: allyloxycarbonyl-   TMS: trimethylsilyl-   TES: triethylsilyl-   TBDMS: tert-butyl(dimethyl)silyl-   PNB: p-nitrobenzyl-   THF: tetrahydrofuran-   ATR: all radiation absorption method

Example 1

According to the present invention, carbapenem compounds selected fromthe following compounds can be prepared.

Example 2

Step a)

To a solution of 4-nitrobenzyl{(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-[2-(3-hydroxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(358 mg) in THF (6 ml) were added at room temperature triethylamine (405mg) and chlorotrimethylsilane (435 mg), and the solution was stirred for1 hour. The reaction solution was poured into ice water. The solutionwas diluted, extracted with ethyl acetate and separated by a separatingfunnel. The organic layer was washed with a cold saturated aqueoussodium chloride solution, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give 4-nitrobenzyl((3S,4R)-2-oxo-4-(2-oxo-2-{3-[(trimethylsilyl)oxy]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.This compound was used in the next step without further purification.

Step b)

Toluene (50 ml) was added to 4-nitrobenzyl ((3 S,4R)-2-oxo-4-(2-oxo-2-{3-[(trimethylsilyl)oxy]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetateprepared in the above step and 2,6-di-tert-butyl-p-cresol (catalyticamount), and the mixture was stirred for 2.5 hours in an oil bath at100° C. Then the temperature was raised to 130° C. and the mixture wasstirred for 6.5 hours. The solvent was removed under reduced pressureand the residue was crystallized from hexane/ethyl acetate, filtered,washed and dried under reduced pressure to give 4-nitrobenzyl(5R,6S)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-3-{3-[(trimethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(218 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.15 (9H, s), 0.25 (9H, s), 1.30 (3H, d, J=6.2Hz), 3.11–3.35 (3H, m), 4.18–4.32 (2H, m), 5.15–5.41 (2H, m), 6.77–6.88(2H, m), 6.90–6.99 (1H, m), 7.12–7.23 (1H, m), 7.44 (2H, d, J=8.9 Hz),8.15 (2H, d, J=8.8 Hz).

Step c)

To a solution of 4-nitrobenzyl(5R,6S)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-3-{3-[(trimethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(207 mg) in acetonitrile (3 ml) was added under ice cooling 0.1Nhydrochloric acid (0.3 ml), and the mixture was stirred for 15 minutes.After the solution was neutralized with a 0.1N aqueous sodiumhydrogencarbonate solution (0.3 ml), further thereto 0.25M phosphatebuffer (10 ml, pH6) and acetonitrile (7 ml) were added. Zinc dust (1.49g) was added thereto and the mixture was vigorously stirred for an hourunder ice cooling and for additional an hour at room temperature. Theinsoluble materials were removed with celite and washed with water andchloroform. Then, the filtrate and the washed solvent were combined toseparate by a separating funnel. The aqueous layer was washed withchloroform, twice separated with a separating funnel and an organicsolvent in the aqueous layer was removed under reduced pressure. Theaqueous solution was purified by polymer chromatography (CHP-20P), andthe fractions eluted with water were collected to be subjected tofreeze-drying to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(14 mg).

¹H NMR (400 MHz, D₂O) δ 1.23 (3H, d, J=6.4 Hz), 2.90–3.04 (1H, m),3.25–3.38 (1H, m), 3.43 (1H, dd, J=2.8 Hz, 5.9 Hz), 4.09–4.27 (2H, m),6.71–6.81 (2H, m), 6.81–6.89 (1H, m), 7.18 (1H, t, J=7.9 Hz).

Example 3

A solution of sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(106 mg) in dry dimethylformamide (4.5 ml) was cooled with ice, andthereto pivaloyloxymethyl iodide (123 mg) was added. The mixture wasstirred for 1 hour at the same temperature. Ethyl acetate and ice waterwere added to the reaction solution, and the mixture was separated witha separating funnel. After the organic layer was washed with a coldsaturated aqueous sodium chloride solution (4 times), it was dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and then the residue was purified by silica gel columnchromatography (chloroform/methanol) to give[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(36 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (9H, s), 1.37 (3H, d, J=6.3 Hz),3.17–3.40 (3H, m), 4.21–4.34 (2H, m), 5.72–5.90 (2H, m), 6.80–6.95 (3H,m), 7.17–7.25 (1H, m).

Example 4

Step a)

In the same manner as Example 1, to a solution of allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[3-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene) acetate (2.30 g) in dichloromethane (46 ml)were added at room temperature 4-(dimethylamino)pyridine (60 mg) andtriethylamine (2.25 g), and thereto. triethylsilyl chloride(1.67 g) wasdropped at 0° C. The solution was stirred at room temperature for 1 hourand then, methanol (3 ml) was added thereto. The solvent was removedunder reduced pressure. To the residue were added water and ethylacetate, and the mixture was separated with a separating funnel. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure to give allyl((3S,4R)-2-oxo-4-[2-oxo-2-(3-{[(triethylsilyl)oxy]methyl}phenyl)ethyl]-3-{(1R)-1-[(triethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step b)

To allyl((3S,4R)-2-oxo-4-[2-oxo-2-(3-{[(triethylsilyl)oxy]methyl}phenyl)ethyl]-3-{(1R)-1-[(triethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetateprepared by the above step was added toluene (100 ml), and the solutionwas stirred in a bath at 130° C. for 2.5 hours. The solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography(hexane/ethyl acetate) to give allyl(5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.44 g).

¹H NMR (400 MHz, CDCl₃) δ 0.59–0.68 (m, 12H), 0.95–0.99 (m, 18H), 1.31(d, 3H, J=6.2 Hz), 3.12–3.32 (m, 3H), 4.22–4.27 (m, 2H), 4.59–4.69 (m,2H), 3.71 (s, 2H), 5.15–5.27 (m, 2H), 5.79–5.87 (m, 1H), 7.23–7.31 (m,4H).

Step c)

Anhydrous trifluoromethanesulfonic acid was added to THF (7 ml) andwater (4 ml), and the solution was adjusted to pH2.2. To the solutionwas added at 0° C. allyl(5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(520 mg). After stirring for 1 hour, thereto was added a saturatedaqueous sodium hydrogencarbonate solution, and the solution wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure to giveallyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.This product was used in the next step without further purification.

Step d)

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared in the above step, sodium 2-ethylhexanoate (242 mg) andtriphenylphosphine (32 mg) were dissolved in THF (10 ml), and thesolution was cooled to 0° C. Thereto tetrakis(triphenylphosphine)palladium(0) (70 mg) was added. Thirty minutes later, thereto hexane (3ml) was added and then the solution was stirred for additional 30minutes. The resulting crystals were filtered under nitrogen atmosphere,and dried under reduced pressure to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(217 mg).

¹H NMR (400 MHz, D₂O) δ 1.23 (d, 3H, J=6.4 Hz), 2.98–3.04 (m, 1H),3.34–3.40 (m, 1H), 3.43–3.45 (m, 1H), 4.16–4.20 (m, 2H), 4.54 (s, 2H),7.22–7.33 (m, 4H).

Example 5

In the same manner as Example 3, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (300 MHz, CDCl₃) δ 1.18 (s, 9H), 1.34 (d, 3H, J=6.2 Hz),3.09–3.34 (m, 3H), 4.17–4.30 (m, 2H), 4.68 (s, 2H), 5.73 (d, 1H, J=5.5Hz), 5.83 (d, 1H, J=5.5 Hz), 7.29–7.36 (m, 4H).

Example 6

In the same manner as Example 3, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (300 MHz, CDCl₃) δ 1.18 (s, 9H), 1.34 (d, 3H, J=6.2 Hz),3.09–3.34 (m, 3H), 4.17–4.30 (m, 2H), 4.68 (s, 2H), 5.73 (d, 1H, J=5.5Hz), 5.83 (d, 1H, J=5.5 Hz), 7.29–7.36 (m, 4H).

Example 7

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(160 mg) prepared by example 4 was dissolved in DMF (2.0 ml), andthereto 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (143 mg) was added at0° C. The mixture was stirred at 0° C. for 1 hour and then thereto icewater was added. The mixture was extracted with ethyl acetate. Theorganic layer was washed three times with a cold saturated aqueoussodium chloride solution, followed by a cold saturated aqueous sodiumhydrogencarbonate solution and a saturated aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure and the residue was purified bypreparative thin-layer chromatography (ethyl acetate/acetone) to give(5-methyl-2-oxo-1,3-dioxo1-4-yl)methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(62 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.3 Hz), 1.76 (broad d, 1H,J=3.9 Hz), 2.13 (s, 3H), 3.19–3.37 (m, 3H), 4.28–4.34 (m, 2H), 4.72–4.73(m, 2H), 4.79 (d, 1H, J=13.9 Hz), 4.93 (d, 1H, J=13.9 Hz), 7.18–7.20 (m,1H), 7.32 (s, 1H), 7.35–7.36 (m, 2H). IR(ATR) 3421(broad), 2968, 2927,2877, 1817, 1770, 1732, 1718, 1437, 1387, 1338, 1267, 1228, 1190, 1030,1009, 768, 696 cm⁻¹

Example 8

Step a)

Allyl(5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(911 mg) prepared by step b) of example 4 was dissolved in THF (13 ml),and thereto water (6 ml) and acetic acid (3 ml) were added at 0° C.After stirring for 30 minutes, a saturated aqueous sodiumhydrogencarbonate solution was added thereto and the solution wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give allyl(5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(535 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.57–0.67 (m, 6H), 0.95–0.99 (m, 9H), 1.30 (d,3H, J=6.2 Hz), 1.76 (broad s, 1H), 3.13–3.33 (m, 3H), 4.23–4.28 (m, 2H),4.59–4.73 (m, 4H), 5.16–5.29 (m, 2H), 5.81–5.90 (m, 1H), 7.26–7.37 (m,4H). IR (KBr) 3522(broad), 2956, 2877, 1779, 1723, 1272, 1203, 1005, 746cm⁻¹

Step b)

Allyl(5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(250 mg) prepared in the above step, was dissolved in dichloromethane(10 ml), and thereto were added N,N-diisopropylethylamine (14 mg) andmethyl isocyanate (276 mg). The mixture was stirred for 1 day,concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform) to give allyl(5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(122 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.62 (q, 2H×3, J=7.8 Hz), 0.97 (t, 3H×3, J=7.8Hz), 1.30 (d, 3H, J=6.2 Hz), 2.82 (d, 3H, J=4.9 Hz), 3.13–3.33 (m, 3H),4.22–4.28 (m, 2H), 4.59–4.72 (m, 3H), 5.09 (s, 2H), 5.16–5.28 (m, 2H),5.81–5.88 (m, 1H), 7.29–7.52 (m, 4H).

Step c)

To a solution of allyl(5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(284 mg) in THF (4 ml) was added a solution of anhydroustrifluoromethanesulfonic acid (0.6 ml) in water (2 ml) at 0° C., and thesolution was stirred for 25 minutes. Thereto was added a cold aqueoussaturated sodium hydrogencarbonate solution and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography(chloroform/methanol) to give allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(139 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.3 Hz), 1.77 (d, 1H, J=4.9Hz), 2.82 (d, 3H, J=4.9 Hz), 3.18–3.34 (m, 3H), 4.25–4.33 (m, 2H),4.59–4.74 (m, 3H), 5.09 (s, 2H), 5.16–5.28 (m, 2H), 5.79–5.88 (m, 1H),7.30–7.36 (m, 4H).

Step d)

In the same manner as step d) of example 4, starting from allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.22 (d, 3H, J=6.4 Hz), 2.61 (s, 3H), 2.99 (dd,1H, J=17.0 Hz, 9.8 Hz), 3.34 (dd, 1H, J=17.0 Hz, 8.5 Hz), 3.42 (dd, 1H,J=6.0 Hz, 2.8 Hz), 4.13–4.24 (m, 2H), 4.99 (s, 2H), 7.21–7.33 (m, 4H).

Example 9

In the same manner as example 3, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 8, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.37 (d, 3H, J=6.3 Hz), 1.86(broad s, 1H), 2.82 (d, 3H, J=4.9 Hz), 3.18–3.36 (m, 3H), 4.25–4.33 (m,2H), 4.78 (broad s, 1H), 5.10 (s, 2H), 5.77 (d, 1H, J=5.5 Hz), 5.84 (d,1H, J=5.5 Hz), 7.26–7.34 (m, 4H). IR(ATR) 3396(broad), 2972, 1701, 1527,1259, 1187, 1120, 1095, 1022, 980, 775, 698 cm⁻¹

Example 10

In the same manner as example 2, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-4-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(43 mg) prepared, there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-4-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(28.7 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (9H, s), 1.37 (3H, d, J=6.3 Hz),3.16–3.33 (3H, m), 4.21–4.31 (2H, m), 5.74–5.91 (2H, m), 6.81 (2H, d,J=8.7 Hz), 7.31 (2H, d, J=8.7 Hz).

Example 11

Step a)

To a solution of 4-nitrobenzyl(5R,6S)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-3-{3-[(trimethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(500 mg) in THF (8.6 ml) was added at −78° C. acetic acid (51 mg).Thereto was dropped 1M tetrabutylammonium fluoride/THF solution (0.86ml), and the mixture was stirred at the same temperature for 15 minutes.The reaction mixture was poured into a mixture of a cold aqueous sodiumhydrogencarbonate (72 mg) and ethyl acetate. The mixture was extractedand separated by a separating funnel. The organic layer was washed witha cold saturated aqueous sodium chloride solution (three times) and coldwater in the order, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to give 4-nitrobenzyl(5R,6S)-3-(3-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.This product was used in the next step without further purification.

Step b)

To a solution of 4-nitrobenzyl(5R,6S)-3-(3-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared in the above step in dichloromethane (10 ml) was addedN,N-diisopropylethylamine (catalytic amount), and thereto was addedunder ice cooling a solution of methyl isocyanate (57 mg) indichloromethane (5 ml). After stirring under ice cooling for 2 hours,the temperature was raised to room temperature and the reaction mixturewas poured into a mixture of ice water and ethyl acetate. The mixturewas extracted and separated with a separating funnel. The organic layerwas washed with cold water (twice) and a cold saturated aqueous sodiumchloride solution in the order, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate) to give4-nitrobenzyl(5R,6S)-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(276 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.15 (9H, s), 1.30 (3H, d, J=6.2 Hz), 2.89,2.91 (total 3H, each s), 3.14–3.36 (3H, m), 4.18–4.31 (2H, m), 4.97 (1H,broad d, J=4.4 Hz), 5.16–5.40 (2H, m), 7.04–7.22 (3H, m), 7.31 (1H, t,J=7.9 Hz), 7.43 (2H, d, J=8.7 Hz), 8.15 (2H, d, J=8.8 Hz).

Step c)

In the same manner as step c) of example 2, starting from 4-nitrobenzyl(5R,6S)-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(270 mg), there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(66 mg).

¹H NMR (400 MHz, D₂O) δ 1.20 (3H, d, J=6.4 Hz), 2.69 (3H, s), 2.94–3.05(1H, m), 3.26–3.37 (1H, m), 3.42 (1H, dd, J=2.8 Hz, 5.9 Hz), 4.10–4.26(2H, m), 6.92–7.04 (2H, m), 7.17 (1H, d, J=7.8 Hz), 7.29 (1H, t, J=7.9Hz).

Example 12

In the same manner as example 3, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(53 mg), there was obtained [(2,2-dimethylpropanoyl)oxy]methyl (5R,S)-6-[(1R)-1-hydroxyethyl]-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(28 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (9H, s), 1.37 (3H, d, J=6.3 Hz), 2.89,2.91 (total 3H, each s), 3.17–3.37 (3H, m), 4.21–4.35 (2H, m), 4.99 (1H,broad d, J=3.4 Hz), 5.74–5.90 (2H, m), 7.06–7.23 (3H, m), 7.33 (1H, t,J=7.9 Hz).

Example 13

In the same manner as step c) of example 2, starting from 4-nitrobenzyl(5R,6S)-3-(4-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(340 mg), there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(112 mg).

¹H NMR (400 MHz, D₂O) δ 1.22 (3H, d, J=6.4 Hz), 2.70 (3H, s), 2.95–3.07(1H, m), 3.29–3.40 (1H, m), 3.42 (1H, dd, J=2.8 Hz, 5.9 Hz), 4.11–4.27(2H, m), 7.02 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.7 Hz).

Example 14

In the same manner as example 3, starting from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(78 mg), there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(40.2 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (9H, s), 1.37 (3H, d, J=6.3 Hz), 2.90,2.91 (total 3H, each s), 3.14–3.36 (3H, m), 4.20–4.35 (2H, m), 5.00 (1H,broad d, J=4.9 Hz), 5.71–5.91 (2H, m), 7.12 (2H, d, J=8.6 Hz), 7.36 (2H,d, J=8.6 Hz).

Example 15

Step a)

In the same manner as step a) of example 2, by usingchlorotriethylsilane (3.20 g) instead of chlorotrimethylsilane andstarting from 4-nitrobenzyl{(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-[2-(4-hydroxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.90 g), there was obtained 4-nitrobenzyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[(triethylsilyl)oxy]phenyl}ethyl)-3-{(1R)-1-[(triethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step b)

The residue prepared in the same manner as step b) of example 2 by using4-nitrobenzyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[(triethylsilyl)oxy]phenyl}ethyl)-3-{(1R)-1-[(triethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetateprepared in the above step, was purified by silica gel columnchromatography (chloroform/acetone after hexane/ethyl acetate) to give4-nitrobenzyl(5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-{4-[(triethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(395 mg, a mixture with about equimolar triethylsilanol). This productwas used in the next step without further purification.

Step c)

The residue prepared in the same manner as step a) of example 11 byusing 4-nitrobenzyl(5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-{4-[(triethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(367 mg, a mixture with about equimolar triethylsilanol), was purifiedby silica gel thin-layer chromatography (hexane/ethyl acetate=2/1) togive 4-nitrobenzyl(5R,6S)-3-(4-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(210 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.55–0.68 (6H, m), 0.96 (9H, t, J=7.9 Hz),1.31 (3H, d, J=6.2 Hz), 3.13–3.31 (3H, m), 4.21–4.31 (2H, m), 5.16–5.43(3H, m), 6.78 (2H, d, J=8.7 Hz), 7.31 (2H, d, J=8.7 Hz), 7.53 (2H, d,J=8.7 Hz), 8.18 (2H, d, J=8.8 Hz).

Step d)

4-Nitrobenzyl(5R,6S)-3-(4-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(200 mg) prepared in the above step was dissolved in dichloromethane(4.5 ml). Thereto were added under ice cooling pyridine in a catalyticamount and trichloroacetyl isocyanate (106 mg), and the mixture wasstirred for 1 hour. The reaction mixture was poured into a mixture ofice water and ethyl acetate. The mixture was extracted and separatedwith a separating funnel. The organic layer was washed with cold water(twice) and a cold saturated aqueous sodium chloride solution in theorder, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure. The residue was dissolved in methanol (13.5 ml)and thereto silica gel (2.7 g) was added. The mixture was stirred for1.5 hours and then, kept in a refrigerator overnight. After the reactionmixture was diluted with chloroform, silica gel was removed byfiltration. The solution was washed with chloroform/methanol (=4/1) andthe solvent was removed under reduced pressure. The residue was purifiedby silica gel thin layer chromatography (chloroform/acetone=9/1) to give4-nitrobenzyl(5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(113 mg).

¹H NMR (400 MHz, CDCl₃) δ 0.53–0.69 (6H, m), 0.96 (9H, t, J=7.9 Hz),1.31 (3H, d, J=6.2 Hz), 3.11–3.35 (3H, m), 4.22–4.35 (2H, m), 5.14–5.43(2H, m), 7.10 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 7.44 (2H, d,J=8.8 Hz), 8.17 (2H, d, J=8.8 Hz).

Step e)

To a solution of 4-nitrobenzyl(5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(110 mg) prepared in the above step in THF (1.9 ml) was added under icecooling acetic acid (11 mg). Then 1M tetrabutylammonium fluoride/THFsolution (0.19 ml) was dropped thereto and the mixture was stirred atthe same temperature for 45 minutes. The residue prepared by the samemanner as step a) of example 11 was purified by silica gel thin-layerchromatography (chloroform/acetone=2/1) to give 4-nitrobenzyl(5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(11 mg).

¹H NMR (400 MHz, CD₃OD) δ 1.31 (3H, d, J=6.3 Hz), 3.15–3.50 (2H, m),3.36 (1H, dd, J=2.8 Hz, 6.8 Hz), 4.07–4.19 (1H, m), 4.25–4.35 (1H, m),5.18–5.40 (2H, m), 7.07 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz), 7.46(2H, d, J=8.8 Hz), 8.16 (2H, d, J=8.8 Hz).

Step f)

In the same manner as step c) of example 2, starting from 4-nitrobenzyl(5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(11 mg), there was obtained sodium(5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(4 mg).

¹H NMR (400 MHz, D₂O) δ 1.22 (3H, d, J=6.4 Hz), 2.93–3.08 (1H, m),3.25–3.40 (1H, m), 3.42 (1H, dd, J=2.8 Hz, 6.0 Hz), 4.10–4.28 (2H, m),7.04 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.7 Hz).

Example 16

Step a)

In the same manner as step b of example 1, by using allyl ((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(94 mg) prepared by reference example 7, there was obtained allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(25 mg).

Step b)

To the compound (25 mg) prepared in the above step a), acetic acid (8μl) and a solution of tributyltin hydride (140 μl) in dichloromethane (2ml) was added at room temperature bis(triphenylphosphine) palladiumchloride (II) (3.6 mg), and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture was added a 0.1N aqueous sodiumhydrogencarbonate solution (10 ml) and the aqueous layer was separated.The organic layer was extracted with water (2×5 ml). The aqueous layerswere combined and washed with dichloromethane. The organic solvent inthe aqueous layer was removed under reduced pressure. The aqueoussolution was purified by polymer chromatography (CHP-20P) and fractionseluted with water alone were collected and subjected to freeze-drying togive sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.4 mg).

¹H NMR (300 MHz, D₂O) δ 1.15 (d, 3H, J=6.2 Hz), 2.53 (s, 3H), 2.91 (dd,1H, J=10.6 Hz, 17.0 Hz), 3.28 (dd, 1H, J=8.8 Hz, 17.0 Hz), 3.35 (dd, 1H,J=2.9 Hz, 5.8 Hz), 4.07–4.14 (m, 4H), 7.06–7.21 (m, 4H). IR (ATR) 3315(broad), 2954, 2924, 1749, 1576, 1456, 1396, 1375, 1259, 1134, 1068,881, 833, 785 cm⁻¹.

Example 17

Step a)

Allyl((2R,3S)-2-{2-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-2-oxoethyl}-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(0.61 g) prepared by reference example 10 and bistrimethylsilylamide(0.34 ml) were dissolved in toluene/dioxane (10 ml/5 ml), and thesolution was refluxed for 6 hours. After being cooled, the solvent wasremoved under reduced pressure and the residue was purified by silicagel column chromatography (chloroform/methanol=10:1) to give allyl(5R,6S)-3-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.24 g) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 0.10 (s, 9H), 1.24 (d, 3H, J=6.2 Hz), 2.64 (d,3H, J=4.8 Hz), 3.07 (dd, 1H, J=9.9 Hz, 18.1 Hz), 3.16 (dd, 1H, J=2.7 Hz,6.6 Hz), 3.20 (dd, 1H, J=18.1 Hz), 4.14–4.20 (m, 2H), 4.23 (d, 2H, J=5.8Hz), 4.43–4.58 (m, 1H), 4.61–4.70 (m, 1H), 5.07 (q, 1H, J=4.8 Hz),5.12–5.16 (m, 1H), 5.22–5.28 (m, 1H), 5.42 (t, 1H, J=5.8 Hz), 5.76–5.86(m, 1H), 7.15–7.17 (m, 2H), 7.21–7.24 (m, 2H).

Step b)

The compound (0.24 g) prepared in step a) was dissolved in THF/water (12ml/3 ml), and thereto was added under ice cooling 1N hydrochloric acidto adjust pH 2.5. The solution was stirred for 1 hour. Thereto wereadded pH 6.86 phosphate buffer (15 ml) and a saturated aqueous sodiumchloride solution (15 ml), and the mixture was extracted with ethylacetate (3×20 ml). The organic layer were combined, dried over magnesiumsulfate, and filtered. The solvent was removed under reduced pressure togive a yellow oil (0.24 g). This oil, triphenylphosphine. (13 mg) andsodium 2-ethylhexanoate (93 mg) were dissolved in THF (6 mL), andthereto was added under ice cooling tetrakis(triphenylphosphine)palladium(0) (29 mg). The mixture was stirred for 1 hour. The resultingsolid was collected by filtration, washed with a small amount of THF,and dried under reduced pressure to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(183 mg) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 1.15 (d, 3H, J=6.3 Hz), 2.54 (d, 3H, J=4.6Hz), 2.85 (dd, 1H, J=9.9 Hz, 15.7 Hz), 3.07 (dd, 1H, J=8.5 Hz, 15.7 Hz),3.12 (dd, 1 H, J=2.8 Hz, 6.6 Hz), 3.88–3.93 (m, 1H), 3.97–4.02 (m, 1H),4.12 (d, 2 H, J=5.8 Hz), 4.99 (d, 1 H, J=5.0 Hz), 6.01 (q, 1 H, J=4.6Hz), 6.56 (t, 1 H, J=6.1 Hz), 7.07–7.09 (m, 2H), 7.38–7.40 (m, 2 H). IR(ATR) 3309, 2931, 1749, 1578, 1560, 1508, 1396, 1254, 1221, 1157, 1130,1072, 808, 789, 669 cm⁻¹.

Example 18

Step a)

In the same manner as step a) of Example 2, by using allyl{(2R,3S)-2-[2-(4-{[(aminocarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(0.83 g) prepared by reference example 11, there was obtained allyl{(2R,3S)-2-[2-(4-{[(aminocarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-({trimethylsilyl}oxy)ethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step b)

In the same manner as step b) of example 2, by using the compoundprepared in step a), there was obtained allyl(5R,6S)-3-(4-{[(aminocarbonyl)amino]methyl}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.14 g)

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.29 (d, 3H, J=6.2 Hz), 3.13(dd, 1H, J=9.9 Hz, 18.1 Hz), 3.21 (dd, 1H, J=2.8 Hz, 6.7 Hz), 3.26 (dd,1H, J=8.9 Hz, 18.1 Hz), 4.19–4.25 (m, 2H), 4.29 (d, 2H, J=5.8 Hz), 4.55(broad s, 2H), 4.58–4.63 (m, 1H), 4.66–4.71 (m, 1H), 5.17–5.21 (m, 1H),5.29–5.34 (m, 1H), 5.38 (t, 1H, J=5.8 Hz), 5.81–5.91 (m, 1H), 7.23–7.25(m, 2H), 7.28–7.30 (m, 2H).

Step c)

In the same manner as in step b) of example 17, by using the compound(0.14 g) prepared in step b), there was obtained crude sodium(5R,6S)-3-(4-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.16 g). The product was purified by polymer chromatography (CHP-20P)and fractions eluted with water alone were collected and subjected tofreeze-drying to give the object compound (0.02 g).

¹H NMR (400 MHz, DMSO-d6) δ 1.21 (d, 3H, J=6.3 Hz), 2.91 (dd, 1H, J=9.8Hz, 15.6 Hz), 3.13 (dd, 1H, J=8.5 Hz, 15.6 Hz), 3.19 (dd, 1 H, J=2.8 Hz,6.6 Hz), 3.95–3.98 (m, 1H), 4.03–4.08 (m, 1H), 4.17 (d, 2H, J=5.9 Hz),5.05 (broad s, 1H), 5.60 (broad s, 2H), 6.56 (t, 1H, J=5.9 Hz),7.13–7.16 (m, 2H), 7.45–7.47 (m, 2H). IR (ATR 3323, 1743, 1655, 1581,1560, 1394, 1340, 1304, 1252, 1221, 1132, 806, 789 cm⁻¹.

Example 19

In the same manner as example 3, from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 17, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.34 (d, 3H, J=6.3 Hz), 2.74 (d,3H, J=4.8 Hz), 3.08 (dd, 1H, J=9.9 Hz, 18.3 Hz), 3.20–3.27 (m, 2H),4.16–4.26 (m, 2H), 4.31 (d, 2H, J=5.7 Hz), 4.86 (q, 1H, J=4.8 Hz), 5.22(t, 1H, J=5.7 Hz), 5.73 (d, 1H, J=5.5 Hz), 5.82 (d, 1H, J=5.5 Hz), 7.21(broad s, 4H). IR (ATR) 3356, 2970, 1774, 1751, 1637, 1558, 1481, 1458,1414, 1338, 1265, 1192, 1153, 1122, 1095, 1022, 991, 978, 943, 816, 752,665 cm⁻¹.

Example 20

In the same manner as example 3, from sodium(5R,6S)-3-(4-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 18, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(4-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CD₃CN) δ 1.05 (s, 9H), 1.10 (d, 3H, J=6.3 Hz), 2.99(dd, 1H, J=10.0 Hz, 18.3 Hz), 3.19 (dd, 1 H, J=2.9 Hz, 6.1 Hz), 3.27(dd, 1H, J=8.8 Hz, 18.3 Hz), 3.34 (d, 1H, J=4.8 Hz), 3.92–4.01 (m, 1H),4.08–4.13 (m, 3H), 4.74 (broad s, 2H), 5.58 (d, 1H, J=5.8 Hz), 5.61 (t,1H, J=6.0 Hz), 5.66 (d, 1H, J=5.8 Hz), 7.10–7.12 (m, 2H), 7.17–7.19 (m,2H). IR (ATR) 3369, 2972, 1768, 1751, 1728, 1655, 1602, 1541, 1481,1458, 1336, 1269, 1194, 1122, 1094, 1022, 991, 978, 750, 667 cm⁻¹.

Example 21

Allyl(5R,6S)-6-{(1R)-1-[(allyloxycarbonyl)oxy]ethyl}-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as example 16 starting from allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by reference example 12, followed by deprotection reaction togive sodium(5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-{(1R)-1-[(allyloxycarbonyl)oxy]ethyl}-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CD₃OD) δ 1.49 (3H, d, J=6.3 Hz), 3.13–3.33 (2H, m),3.42 (1H, dd, J=2.8 Hz, 8.5 Hz), 4.28 (1H, dt, J=2.8 Hz, 9.4 Hz),4.55–4.78 (5H, m), 5.11 (2H, s), 5.12–5.42 (5H, m), 5.80–6.00 (2H, m),7.35 (4H, s).

Sodium(5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.22 (3H, d, J=6.4 Hz), 2.93–3.05 (1H, m),3.28–3.40 (1H, m), 3.42 (1H, dd, J=2.8 Hz, 6.0 Hz), 4.10–4.27 (2H, m),5.00 (2H, s), 7.29 (4H, s).

Example 22

A solution of sodium(5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(13 mg) in dry dimethylformamide (0.5 ml) was cooled with ice, andthereto were added N,N-diisopropylethylamine (5 mg),benzyltriethylammonium chloride (5 mg) and pivaloyloxymethyl chloride(11 mg). The mixture was gradually warmed to room temperature andstirred for overnight. To the reaction mixture were added ethyl acetateand ice water to separate by a separating funnel. The organic layer waswashed with cold water (three times) and a cold saturated aqueous sodiumchloride solution (twice), and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel thin-layer chromatography (ethyl acetate) to give[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(9.2 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (9H, s), 1.37 (3H, d, J=6.3 Hz),3.15–3.38 (3H, m), 4.20–4.35 (2H, m), 4.73 (2H, broad s), 5.11 (2H, s),5.74–5.90 (2H, m), 7.35 (4H, s).

Example 23

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-[5-({[(allyloxy)carbonyl]oxy}methyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as example 16, starting from allyl((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[5-({[(allyloxy)carbonyl]oxy}methyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetateprepared by reference example 14, followed by deprotection reaction togive sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[5-(hydroxymethyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-[5-({[(allyloxy)carbonyl]oxy}methyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.48 (d, 3H, J=6.3 Hz), 3.28–3.46(m, 3H), 4.22(td, 1H, J=9.4, 2.8 Hz), 4.63–4.65 (m, 4H), 4.72–4.78 (m, 1H), 4.83–4.89(m, 1H), 5.14–5.18 (m, 1H), 5.25–5.49 (m, 8H), 5.87–6.03 (m, 3H), 7.09(d, 1H, J=3.9 Hz), 7.43 (d, 1H, J=3.9 Hz).

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[5-(hydroxymethyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.21 (d, 3H, J=6.4 Hz), 3.17–3.29 (m, 2H), 3.38(dd, 1H, J=5.9 Hz, 2.7 Hz), 4.13–4.18 (m, 2H), 4.66 (s, 2H), 6.89 (d,1H, J=3.6 Hz), 7.02 (d, 1H, J=3.6 Hz). IR(ATR) 3267(broad), 2968, 1734,1593, 1387, 1300, 1254, 1227, 1132, 1007, 802 cm⁻¹

Example 24

In the same manner as example 3, from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[5-(hydroxymethyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(108 mg), there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[5-(hydroxymethyl)thien-2-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(114 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (s, 9H), 1.37 (d, 3H, J=6.3 Hz), 1.80 (d,1H, J=4.7 Hz), 1.92 (t, 1H, J=6.1 Hz), 3.20 (dd, 1H, J=6.8 Hz, 2.8 Hz),3.31–3.49 (m, 2H), 4.21–4.29 (m, 2H), 4.84 (d, 2H, J=5.9 Hz), 5.91 (d,1H, J=5.5 Hz), 5.99 (d, 1H, J=5.5 Hz), 7.00 (d, 1H, J=3.9 Hz), 7.47 (d,1H, J=3.9 Hz). IR(ATR) 3408(broad), 2972, 1751, 1271, 1189, 1093, 1022,985, 802 cm⁻¹

Example 25

Step a)

In the same manner as step a) and step b) of example 2, from allyl[(2R,3S)-2-[2-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate,there was obtained allyl(5R,6S)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.30 (d, 3H, J=6.1 Hz),3.15–3.30 (m, 3H), 4.17–4.24 (m, 2H), 4.64–4.73 (m, 4H), 5.17–5.40 (m,4H), 5.86–6.00 (m, 2H), 6.76 (s, 1H), 7.32–7.40 (m, 4H).

Step b), Step c)

Allyl(5R,6S)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as step b) of example 17 bydetrimethylsilyletherification of allyl(5R,6S)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateand then, the product was treated in the same manner as step b) ofexample 16 to give sodium(5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.3 Hz), 3.17–3.30 (m, 3H),4.22–4.30 (m, 2H), 4.64–4.74 (m, 4H), 5.17–5.40 (m, 4H), 5.84–5.98 (m,2H), 6.73 (s, 1H), 7.34–7.38 (m, 4H).

Sodium(5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.40 (d, 3H, J=6.4 Hz), 3.13 (dd, 1H, J=16.9 Hz,9.7 Hz), 3.48 (dd, 1H, J=16.9 Hz and 8.6 Hz), 3.53–3.58 (m, 1H),4.30–4.39 (m, 2H), 6.85–6.93 (m, 2H), 7.28–7.33 (m, 2H).

Example 26

In the same manner as example 3, by using sodium(5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (s, 9H), 1.36 (d, 3H, J=6.3 Hz),3.16–3.26 (m, 3H), 3.89 (broads, 2H), 4.18–4.30 (m, 2H), 5.81 (d, 1H,J=5.5 Hz), 5.90 (d, 1H, J=5.5 Hz), 6.62 (d, 2H, J=8.6 Hz), 7.28 (d, 2H,J=8.6 Hz).

Example 27

Step a)

In the same manner as step a) and step b) of example 2, from allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate,there was obtained allyl(5R,6S)-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 0.14 (s, 9H), 1.30 (d, 3H, J=6.2 Hz), 2.76 (d,3H, J=4.8 Hz), 3.15–3.28 (m, 3H), 3.57 (s, 2H), 4.21–4.26 (m, 2H),4.64–4.67 (m, 1H), 4.70–4.74 (m, 1H), 5.17–5.22 (m, 1H), 5.28–5.35 (m,1H), 5.46 (broads, 1H), 5.82–5.90 (m, 1H), 7.26 (d, 2H, J=8.1 Hz), 7.36(d, 2H, J=8.1 Hz).

Step b), Step c)

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as step b) of example 17 bydetrimethylsilyletherification of allyl(5R,6S)-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateand then, the product was treated in the same manner as step d) ofexample 4 to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{,4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.3 Hz), 2.11 (brs, 1H), 2.77(d, 3H, J=4.8 Hz), 3.18–3.30 (m, 3H), 3.57 (s, 2H), 4.26–4.32 (m, 2H),4.64–4.67 (m, 1H), 4.70–4.74 (m, 1H), 5.17–5.22 (m, 1H), 5.26–5.34 (m,1H), 5.46 (broads, 1H), 5.83–5.93 (m, 1H), 7.24 (d, 2H, J=8.2 Hz), 7.36(d, 2H, J=8.2 Hz).

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.14 (d, 3H, J=6.5 Hz), 2.58 (s, 3H), 2.95 (dd,1H, J=17.0 Hz, 9.8 Hz), 3.31 (dd, 1H, J=17 Hz, 8.5 Hz), 3.36–3.40 (m,1H), 3.46 (s, 2H), 4.10–4.22 (m, 2H), 7.13 (d, 2H, J=8.2 Hz), 7.21 (d,2H, J=8.2 Hz).

Example 28

In the same manner as example 3, by using sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.38 (d, 3H, J=6.3 Hz), 2.48 (d,3H, J=4.8 Hz), 3.15–3.35 (m, 3H), 3.60 (s, 2H), 4.24–4.34 (m, 2H), 5.65(broads, 1H), 5.73 (d, 1H, J=5.5 Hz), 5.82 (d, 1H, J=5.5 Hz), 7.24 (d,2H, J=8.2 Hz), 7.29 (d, 2H, J=8.2 Hz).

Example 29

Step a)

In the same manner as step a) and step b) of example 2, from allyl[(2R,3S)-2-{2-[4-(2-amino-2-oxoethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate, there was obtained allyl(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, ODCl₃) δ 0.15 (s, 9H), 1.30 (d, 3H, J=6.2 Hz),3.15–3.28 (m, 3H), 3.58 (s, 2H), 4.20–4.25 (m, 2H), 4.63–4.67 (m, 1H),4.68–4.72 (m, 1H), 5.17–5.22 (m, 1H), 5.27–5.33 (m, 1H), 5.52 (broads,1H), 5.82–5.90 (m, 1H), 7.25–7.28 (m, 2H), 7.36 (d, 2H, J=8.2 Hz).

Step b), Step c)

Allyl(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as step b) of example 17 bydetrimethylsilyletherification of allyl(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-7-oxo-6-{(1R)-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateand then, the product was treated in the same manner as step d) ofexample 4 to give sodium(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

allyl(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (300 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.2 Hz), 3.14–3.35 (m, 3H),3.59 (s, 2H), 4.22–4.35 (m, 2H), 4.60–4.68 (m, 1H), 4.69–4.77 (m, 1H),5.17–5.22 (m, 1H), 5.25–5.34 (m, 1H), 5.44 (broads, 1H), 5.80–5.94 (m,1H), 7.25–7.28 (m, 2H), 7.37 (d, 2H, J=8.2 Hz).

Sodium(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.12 (d, 3H, J=6.4 Hz), 2.89 (dd, 1H, J=17.0 Hz,9.8 Hz), 3.25 (dd, 1H, J=17 Hz, 8.5 Hz), 3.28–3.34 (m, 1H), 3.43 (s,2H), 4.04–4.16 (m, 2H), 7.09 (d, 2H, J=8.2 Hz), 7.16 (d, 2H, J=8.2 Hz).

Example 30

In the same manner as example 3, by using sodium(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-[4-(2-amino-2-oxoethyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.37 (d, 3H, J=6.3 Hz),3.16–3.35 (m, 3H), 3.60 (s, 2H), 4.26–4.35 (m, 2H), 5.32 (broads, 1H),5.41 (broads, 1H), 5.73(d, 1H, J=5.5 Hz), 5.82 (d, 1H, J=5.5 Hz),7.25–7.34 (m, 4H).

Example 31

Step a)

In the same manner as step a) and step b) of example 2, by using allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{3-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate,there was obtained allyl(5R,6S)-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.30 (d, 3H, J=6.1 Hz), 2.76 (d,3H, J=4.8 Hz), 3.18–3.28 (m, 3H), 3.57 (s, 2H), 4.19–4.25 (m, 2H),4.62–4.67 (m, 1H), 4.67–4.72 (m, 1H), 5.17–5.23 (m, 1H), 5.29–5.36 (m,1H), 5.72 (broads, 1H), 5.80–5.95 (m, 1H), 7.24–7.30 (m, 3H), 7.32–7.39(m, 1H).

Step b), Step c)

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as step b) of example 17 bydetrimethylsilyletherification of allyl(5R,6S)-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateand then, the product was treated in the same manner as step of d) ofexample 4 to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.30 (d, 3H, J=6.1 Hz), 2.77 (d, 3H, J=4.8Hz), 3.22–3.32 (m, 3H), 3.58 (s, 2H), 4.25–4.34 (m, 2H), 4.62–4.67 (m,1H), 4.67–4.74 (m, 1H), 5.18–5.25 (m, 1H), 5.29–5.36 (m, 1H), 5.72(broads, 1H), 5.85–5.95 (m, 1H), 7.20–7.30 (m, 3H), 7.32–7.39 (m, 1H).

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.18 (d, 3H, J=6.4 Hz), 2.93 (s, 3H), 2.92–3.01(m, 1H), 3.28–3.36 (m, 1H), 3.38–3.42 (m, 1H), 3.47 (s, 2H), 4.12–4.24(m, 2H), 7.08–7.15 (m, 2H), 7.16–7.20 (m, 1H), 7.22–7.28 (m, 1H).

Example 32

In the same manner as example 3, by using sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate,there was obtained [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{3-[2-(methylamino)-2-oxoethyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.38 (d, 3H, J=6.3 Hz), 2.78 (d,3H, J=4.8 Hz), 3.21–3.57 (m, 3H), 3.59 (s, 2H), 4.25–4.34 (m, 2H), 5.77(d, 1H, J=5.5 Hz), 5.81 (broads, 1H), 5.84 (d, 1H, J=5.5 Hz), 7.15–7.27(m, 3H), 7.30–7.37 (m, 1H).

Example 33

Step a)

In the same manner as step a) of example 2, by using allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[({[(5-methyl-2-oxo-1,3-dioxo-4-yl)methoxy]carbonyl}amino)methyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(0.52 g) prepared by reference example 26, there was obtained allyl[(2R,3S)-3-[(1R)-1-({trimethylsilyl}oxy)ethyl]-2-(2-{4-[({[(5-methyl-2-oxo-1,3-dioxo-4-yl)methoxy]carbonyl}amino)methyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step b)

In the same manner as step b) of example 2, by using a compound preparedin the above step, there was obtained allyl(5R,6S)-3-{4-[({[(5-methyl-2-oxo-1,3-dioxo-4-yl)methoxy]carbonyl}amino)methyl]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.21 g).

¹H NMR (400 MHz, CDCl₃) δ 1.30 (d, 3H, J=6.2 Hz), 2.19 (s, 3H), 3.16(dd, 1H, J=9.9 Hz, 18.1 Hz), 3.22 (dd, 1H, J=2.8 Hz, 6.9 Hz), 3.28 (dd,1H, J=8.9 Hz, 18.1 Hz), 4.19–4.25 (m, 2H), 4.36 (d, 2H, J=6.0 Hz),4.60–4.65 (m, 1H), 4.69–4.74 (m, 1H), 4.84 (s, 2H), 5.17–5.21 (m, 1H),5.28–5.33 (m, 1H), 5.30 (broad s, 1H), 5.82–5.92 (m, 1H), 7.25–7.27 (m,2H), 7.33–7.36 (m, 2H).

Step c)

In the same manner as step b) of example 17, by using the compound (0.05g) prepared in the above step b), there was obtained crude sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[({[(5-methyl-2-oxo-1,3-dioxo-4-yl)methoxy]carbonyl}amino)methyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.01 g), and the crude product was purified by polymer chromatography(CHP-20P) and fractions eluted with THF 2˜8% were collected andsubjected to freeze-drying to give the object compound (0.01 g).

LC/MS (EI) 459 (M+1)+. ¹H NMR (400 MHz, DMSO-d6) δ 1.09 (d, 3H, J=6.2Hz), 2.08 (s, 3H), 2.78 (dd, 1H, J=10.0 Hz, 15.6 Hz), 3.00 (dd, 1H,J=8.6 and 15.6 Hz), 3.06 (dd, 1H, J=2.7 Hz, 6.5 Hz), 3.81–3.83 (m, 1H),3.85–3.88 (m, 1H), 4.07 (d, 2H, J=5.9 Hz), 4.82 (s, 2H), 4.92 (br, 1H),7.01–7.03 (m, 2H), 7.32–7.34 (m, 2H), 7.84 (t, 1H, J=5.9 Hz). IR (ATR)3348 (broad), 1817, 1736, 1718, 1591, 1518, 1394, 1308, 1252, 1227,1196, 1132, 1038, 1011, 984, 769 cm⁻¹.

Example 34

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as example 16 starting from allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by reference example 27 and then, the product was subjected todeprotection reaction to give sodium(5R,6S)-3-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-(3-{{[(aminocarbonyl)oxy]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.49 (d, 3H, J=6.3 Hz), 3.17–3.33 (m, 2H),3.42 (dd, 1H, J=8.4, 2.8 Hz), 4.26–4.31 (m, 1H), 4.59–4.73 (m, 6H), 5.09(s, 2H), 5.15–5.40 (m, 5H), 5.80–5.98 (m, 2H), 7.30–7.37 (m, 4H).IR(ATR) 3178(broad), 2981(broad), 1778, 1720, 1331, 1257, 1180, 748, 721cm⁻¹. LC/MS (EI) 471 (M+1)+.

Sodium(5R,6S)-3-(3-{f[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.23 (d, 3H, J=6.4 Hz), 3.00 (dd, 1H, J=17.0,9.8 Hz), 3.36 (dd, 1H, J=17.0, 8.5 Hz), 3.44 (dd, 1H, J=6.0, 2.8 Hz),4.16–4.26 (m, 2H), 4.72 (s, 2H), 7.23–7.33 (m, 4H). IR(ATR) 3336(broad),2966, 1709, 1589, 1392, 1335, 1049, 787, 698 cm⁻¹.

Example 35

In the same manner as example 3, from sodium(5R,6S)-3-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 34, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.17 (s, 9H), 1.36 (d, 3H, J=6.3 Hz), 1.97(br-s, 1H), 3.19–3.36 (m, 3H), 4.25–4.33 (m, 2H), 4.74 (br-s, 2H), 5.10(s, 2H), 5.77 (d, 1H, J=5.5 Hz), 5.84 (d, 1H, J=5.5 Hz), 7.28–7.37 (m,4H). IR(ATR) 3460(broad), 3367(broad), 2974, 1713, 1331, 1265, 1122,1095, 1049, 1022, 980, 787, 698 cm⁻¹. LC/MS (EI) 461 (M+1)+.

Example 36

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-{4-[(formylamino)methyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate wasprepared in the same manner as example 16 starting from allyl[(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-(2-{4-[(formylamino)methyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetateprepared by reference example 28 and then, the product was subjected todeprotection reaction to give sodium(5R,6S)-3-{4-[(formylamino)methyl]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-{4-[(formylamino)methyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.42 (d, 3H, J=6.3 Hz), 3.21–3.29 (m, 1H),3.56 (dd, 1H, J=18.1, 8.6 Hz), 3.71 (dd, 1H, J=6.5, 3.0 Hz), 4.33–4.38(m, 1H), 4.44 (d, 2H, J=6.3 Hz), 4.57–4.70 (m, 4H), 5.11–5.18 (m, 2H),5.23–5.39 (m, 3H), 5.83–6.02 (m, 2H), 7.29–7.31 (m, 2H), 7.39–7.41 (m,2H), 7.62 (br-s, 1H), 8.26 (d, 1H, J=0.5 Hz). IR(ATR) 3375(broad), 2939,1774, 1743, 1720, 1670, 1373, 1335, 1254, 1192, 1138, 1107, 945, 752cm⁻¹. LC/MS (EI) 455 (M+1)+.

Sodium(5R,6S)-3-{4-[(formylamino)methyl]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.22 (d, 3H, J=6.4 Hz), 2.99 (dd, 1H, J=16.9,7.8 Hz), 3.35 (dd, 1H, J=17.0, 8.5 Hz), 3.42 (dd, 1H, J=6.0, 2.8 Hz),4.16–4.35 (m, 2H), 4.72 (s, 1.76H), 4.77 (s, 0.24H), 7.21 (d, 2H, J=8.4Hz), 7.26–7.28 (m, 2H), 8.06 (s, 0.12H), 8.08 (s, 0.88H). IR(ATR)3248(broad), 2974, 1743, 1659, 1585, 1385, 1308, 1242, 1223, 1130, 671cm⁻¹.

Example 37

In the same manner as example 3, from sodium(5R,6S)-3-{4-[(formylamino)methyl]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 36, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-{4-[(formylamino)methyl]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.37 (d, 3H, J=5.6 Hz), 1.88(br-s, 1H), 3.17–3.34 (m, 3H), 4.24–4.33 (m, 2H), 4.44 (d, 0.3H, J=6.6Hz), 4.50 (d, 1.7H, J=5.8 Hz), 5.74–5.77 (m, 1H), 5.83–5.86 (m, 1H),5.95 (br-s, 1H), 7.29–7.36 (m, 4H), 8.19–8.28 (m, 1H). IR(ATR)3367(broad), 2974, 2935, 2873, 1774, 1747, 1662, 1269, 1122, 1095, 1022,991, 980 cm⁻¹. LC/MS (EI) 445 (M+1)+.

Example 38

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas prepared in the same manner as example 16 from allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by reference example 29 and then, the product was subjected todeprotection reaction to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Allyl(5R,6S)-6-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 1.48 (d, 3H, J=6.3 Hz), 3.15–3.30 (m, 2H),3.40–3.42 (m, 1H), 3.71 (s, 3H), 4.25–4.30 (m, 1H), 4.37 (d, 2H, J=6.0Hz), 4.60–4.66 (m, 3H), 4.69–4.75 (m, 1H), 5.02 (br-s, 1H), 5.13–5.22(m, 2H), 5.26–5.28 (m, 1H), 5.30–5.31 (m, 1H), 5.34–5.40 (m, 1H),5.82–5.99 (m, 2H), 7.27 (d, 2H, J=8.3 Hz), 7.33 (d, 2H, J=8.3 Hz).IR(ATR) 3251(broad), 2947, 1778, 1743, 1716, 1254, 748, 721 cm⁻¹. LC/MS(EI) 485 (M+1)+.

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.22 (d, 3H, J=6.4 Hz), 2.96–3.03 (m, 1H),3.32–3.38 (m, 1H), 3.41–3.43 (m, 1H), 3.58 (s, 3H), 4.14–4.24 (m, 4H),7.20 (d, 2H, J=8.4 Hz), 7.25–7.27 (m, 2H). IR(ATR) 3302(broad), 2966,1747, 1693, 1589, 1551, 1389, 1261 cm⁻¹.

Example 39

In the same manner as example 3, from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 38, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.37 (d, 3H, J=6.3 Hz), 1.85(br-s, 1H), 3.16–3.34 (m, 3H), 3.71 (s, 3H), 4.25–4.32 (m, 2H), 4.38 (d,2H, J=5.9 Hz), 5.06 (br-s, 1H), 5.76 (d, 1H, J=5.5 Hz), 5.85 (d, 1H,J=5.5 Hz), 7.26–7.33 (m, 4H). IR(ATR) 3390(broad), 2974, 1701, 1527,1261, 1192, 1122, 1095, 1022, 991, 980, 775 cm⁻¹. LC/MS (EI) 475 (M+1)+.

Example 40

Step a)

In the same manner as step b) of example 2, from allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(3.32 g) prepared by reference example 32, there was obtained allyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(2.80 g). The product without purification was treated in the samemanner as step b) of example 2 to give allyl(5R,6S)-7-oxo-3-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}-6-{(1R)-1-[(-[(trimethylsilyl)oxy]ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(2.86 g).

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.30 (d, 3H, J=6.0 Hz),3.15–3.28 (m, 3H), 4.19–4.23 (m, 2H), 4.65–4.73 (m, 2H), 5.19–5.35 (m,2H), 5.85–5.95 (m, 1H), 7.50–7.56 (m, 2H), 8.18(s, 1H), 8.22(d, 1H,J=8.0 Hz), 9.10 (s, 1H).

Step b)

In the same manner as step b) of example 17, from the compound (1.43 g)prepared in the above step, there was obtained allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.49 g).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.0 Hz), 3.24–3.30 (m, 3H),4.26–4.31 (m, 2H), 4.66–4.74 (m, 2H), 5.20–5.35 (m, 2H), 5.86–6.00 (m,1H), 7.44 (d, 2H, J=8.4 Hz), 7.67 (d, 2H, J=8.4 Hz), 7.99 (s, 1H), 8.25(d, 1H, J=7.6 Hz), 8.80 (d, 1H, J=6.4 Hz), 9.14 (s, 1H).

Step c)

In the same manner as step b) of example 17, from the compound (0.49 g)prepared in the above step, there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.28 g).

¹H NMR (400 MHz, D₂O) 61.12 (d, 3H, J=6.4 Hz), 2.92 (dd, 1H, J=16.8 Hz,9.8 Hz), 3.26 (dd, 1H, J=16.8 Hz, 8.4 Hz), 3.31–3.33 (m, 1H), 4.05–4.14(m, 2H), 7.23 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.40–7.43 (m,1H), 8.10 (d, 1H, J=8.0 Hz), 8.53(d, 1H, J=2.0 Hz), 8.79 (d, 1H, J=8.0Hz).

Step d)

In the same manner as example 3, from the compound (0.22 g) prepared inthe above step, there was obtained [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.17 g).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.37 (d, 3H, J=6.0 Hz),3.20–3.37 (m, 3H), 4.25–4.33 (m, 2H), 5.78 (d, 1H, J=5.6 Hz), 5.87 (d,1H, J=5.6 Hz), 7.42 (d, 2H, J=8.8 Hz), 7.47–7.51 (m, 1H), 7.67 (d, 2H,J=8.8 Hz), 8.80 (s, 1H), 8.24 (d, 1H, J=6.8 Hz), 8.79 (d, 1H, J=3.6 Hz),9.13 (s, 1H).

Example 41

Step a)

In the same manner as step b) of example 2, from allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[4-(isonicotinoylamino)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(2.15 g) prepared by reference example 33, there was obtained allyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-(isonicotinoylmino)phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(2.16 g). The product without purification was treated in the samemanner as step b) of example 2 to give allyl(5R,6S)-3-[4-(isonicotinoylamino)phenyl]-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(2.35 g).

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.30 (d, 3H, J=6.0 Hz),3.15–3.30 (m, 3H), 4.17–4.25 (m, 2H), 5.19–5.35 (m, 2H), 5.83–5.95 (m,1H), 7.13–7.15 (m, 2H), 7.75–7.77 (m, 2H), 7.99–8.01 (m, 2H), 8.18 (s,1H), 8.78–8.80 (m, 2H).

Step b)

In the same manner as step b) of example 17, from the compound (1.18 g)prepared in the above step, there was obtained allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(isonicotinoylamino)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.25 g).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.4 Hz), 3.20–3.12 (m, 3H),4.20–4.33 (m, 2H), 4.61–4.80 (m, 2H), 5.20–5.35 (m, 2H), 5.85–5.93 (m,1H), 7.45 (d, 2H, J=8.8 Hz), 7.65 (d, 2H, J=8.8 Hz), 7.72–7.73 (d, 2H,J=8.8 Hz), 7.90 (s, 1H), 8.89–8.90 (m, 2H).

Step c)

In the same manner as step b) of example 17, from the compound (0.25 g)prepared in the above step, there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[4-(isonicotinoylamino)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.19 g).

¹H NMR (400 MHz, D₂O) δ 1.23 (d, 3H, J=6.4 Hz), 2.96–3.03 (m, 1H),3.31–3.37 (m, 3H), 3.40–3.43 (m, 1H), 4.16–4.22 (m, 2H), 7.27 (s, 4H).

Step d)

In the same manner as example 3, from the compound (0.12 g) prepared inthe above step, there was obtained [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[4-(isonicotinoylamino)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H), 1.37 (d, 3H, J=6.0 Hz),3.23–3.35 (m, 3H), 4.26–4.30 (m, 2H), 5.79 (d, 1H, J=5.6 Hz), 5.88 (d,1H, J=5.6 Hz), 7.42 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.72 (d,2H, J=6.0 Hz), 7.95 (s, 1H), 8.83 (d, 2H, J=6.0 Hz).

Example 42

Step a)

In the same manner as step b) of example 2, from allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetateprepared by reference example 34, there was obtained allyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.The product without purification was treated in the same manner as stepb) of example 2 to give allyl(5R,6S)-7-oxo-3-{4-[(pyridin-2-ylcarbonyl)amino)phenyl)-6-{(1R)-1-[(-[(trimethylsilyl)oxy]ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.31 (d, 3H, J=6.0 Hz),3.12–3.35 (m, 3H), 4.15–4.25 (m, 2H), 4.60–4.67 (m, 2H), 5.19–5.34 (m,2H), 5.85–5.95 (m, 1H), 7.44 (d, 2H, J=8.4 Hz), 7.48–7.51 (m, 1H), 7.78(d, 2H, J=8.4 Hz), 7.80–7.94 (m, 1H), 8.30 (d, 1H, J=7.6 Hz), 8.63 (d,1H, J=4.4 Hz).

Step b)

In the same manner as step b) of example 17, from the compound preparedin the above step, there was obtained allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.0 Hz), 3.24–3.31 (m, 3H),4.21–4.34 (m, 2H), 4.60–4.83 (m, 2H), 5.18–5.36 (m, 2H), 5.80–5.91 (m,1H), 7.41–7.52 (m, 2H), 7.77–7.82 (m, 2H), 7.92–7.94 (m, 1H), 8.30 (d,1H, J=4.0 Hz), 8.63 (d, 1H, J=4.4 Hz), 10.09–10.13 (m, 1H).

Step c)

In the same manner as step b) of example 17, from the compound preparedin the above step, there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, D₂O) δ 1.12 (d, 3H, J=6.4 Hz), 2.91 (dd, 1H, J=16.8 Hz,9.6 Hz), 3.22–3.33 (m, 2H), 4.03–4.14 (m, 2H), 7.23 (d, 2H, J=8.8 Hz),7.42–7.47 (m, 3H), 7.85–7.87 (m, 1H), 7.93 d, 1H, J=8.0 Hz), 8.48 (d,1H, J=4.4 Hz).

Step d)

In the same manner as example 3, from the compound prepared in the abovestep, there was obtained [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H), 1.37 (d, 3H, J=6.0 Hz),3.22–3.48 (m, 3H), 4.27–4.33 (m, 2H), 5.80 (d, 1H, J=5.6 Hz), 5.89 (d,1H, J=5.6 Hz), 7.44 (d, 2H, J=8.8 Hz), 7.49–7.52 (m, 1H), 7.79 (d, 2H,J=8.8 Hz),7.90–7.95 (m, 1H), 8.30 (d, 1H, J=8.0 Hz), 8.63 (d, 1H, J=4.0Hz), 10.13 (s, 1H).

Example 43

Step a)

In the same manner as step b) of example 2, from allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[(methoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate (2.64 g) prepared by reference example 35, there was obtainedallyl((2R,3S)-2-(2-{4-[(methoxycarbonyl)amino]phenyl}-2-oxoethyl)-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate (2.59 g).The product without purification is treated in the same manner as stepb) of example 2 to give allyl(5R,6S)-3-{4-[(methoxycarbonyl)amino]phenyl}-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(2.66 g).

LC/MS (EI) 459 (M+1)

Step b)

In the same manner as step b) of example 17 from the compound (1.33 g)prepared in the above step, there was obtained allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methoxycarbonyl)amino]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.29 g).

¹H NMR (400 MHz, CDCl₃) δ 1.26 (d, 3H, J=6.4 Hz), 3.05–3.20 (m, 3H),3.67 (s, 3H), 4.14–4.22 (m, 2H), 4.50–4.68 (m, 2H), 5.08–5.22 (m, 2H),5.74–5.81 (m, 1H), 6.55 (s, 1H), 7.20–7.28 (m, 4H).

Step c)

In the same manner as step b) of example 17, from the compound (0.29 g)prepared in the above step, there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methoxycarbonyl)amino]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.11 g).

¹H NMR (400 MHz, D₂O) δ 1.11 (d, 3H, J=6.4 Hz), 2.87–2.94 (m, 1H),3.21–3.32 (m, 3H), 4.04–4.12 (m, 2H), 7.22 (d, 2H, J=8.4 Hz), 7.34 (d,2H, J=8.4 Hz), 7.49 (s, 1H), 7.72 (d, 2H, J=6.0 Hz), 8.52 (d, 2H, J=6.0Hz).

Step d)

In the same manner as example 3, from the compound (0.15 g) prepared inthe above step, there was obtained [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methoxycarbonyl)amino]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.11 g).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.36 (d, 3H, J=6.4 Hz),3.18–3.33 (m, 3H), 3.78 (s, 3H), 4.24–4.32 (m, 2H), 5.78 (d, 1H, J=5.6Hz), 5.87 (d, 1H, J=5.6 Hz), 6.68 (s, 1H), 7.30–7.38 (m, 4H).

Example 44

A mixture of [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 26, diisopropylethylamine and dichloromethane wascooled at 0° C., and thereto was dropped acetyl chloride. Afterstirring, the reaction mixture was poured into ice water. The mixturewas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution in the order, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure to give acrude product. The crude product was purified by silica gelchromatography, to give [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-3-[4-(acetylamino)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

LC/MS (EI) 459 (M+1)

Example 45

Step a)

In the same manner as step b) of example 2, from allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{3-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetateprepared by reference example 38, there was obtained allyl((3S,4R)-2-oxo-4-(2-oxo-2-{3-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.The product without purification was treated in the same manner as stepb) of example 2 to give allyl(5R,6S)-7-oxo-3-{3-[(pyridin-3-ylcarbonyl)amino)phenyl)-6-{(1R)-1-[(-[(trimethylsilyl)oxy]ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

LC/MS (EI) 506 (M+1)

Step b)

In the same manner as step b) of example 17, from the compound preparedin the above step, there was obtained allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{3-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.37 (d, 3H, J=6.0 Hz), 3.20–3.38 (m, 3H),4.26–4.38 (m, 2H), 4.60–4.78 (m, 2H), 5.16–5.30 (m, 2H), 5.82–5.89 (m,1H), 7.16 (d, 1H, J=6.8 Hz), 7.37 (t, 1H, J=8.0 Hz), 7.44–7.48 (m, 1H),7.48 (s, 1H), 7.72 (s, 1H), 8.07 (s, 1H), 8.22 (d, 1H, J=8.0 Hz), 8.78(d, 1H, J=6.4 Hz), 9.09(s, 1H).

Step c)

In the same manner as step b) of example 17, from the compound preparedin the above step, there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{3-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, D₂O) δ 1.13 (d, 3H, J=6.4 Hz), 2.94 (dd, 1H, J=17.6 Hz,7.6 Hz), 3.28 (dd, 1H, J=17.2 Hz, 8.8 Hz), 3.33–3.35 (m, 1H), 4.06–4.16(m, 2H), 7.08 (d, 2H, J=8.4 Hz), 7.25 (d, 1H, J=8.0 Hz), 7.29 (s, 3H),7.34 (d, 1H, J=7.6 Hz), 7.42–7.45 (m, 1H), 8.12 (s, 1H), 8.54 (d, 1H,J=4.4 Hz), 8.81 (s, 1H).

Step d)

In the same manner as example 3, from the compound prepared in the abovestep, there was obtained [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{3-[(pyridin-3-ylcarbonyl)amino]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.14 (s, 9H), 1.37 (d, 3H, J=6.4 Hz),3.24–3.42 (m, 3H), 4.26–4.33 (m, 2H), 5.75 (d, 1H, J=5.6 Hz), 5.82 (d,1H, J=5.6 Hz), 7.09 (d, 1H, J=6.8 Hz), 7.38–7.46 (m, 3H), 8.32 (d, 1H,J=6.0 Hz), 8.71 (s, 1H), 8.78 (d, 1H, J=6.0 Hz), 9.24 (s, 1H).

Example 46

In the same manner as step b) of example 2, by usingbistrimethylsilylamide as an additive and from allyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(0.62 g) prepared by reference example 39, there was obtained allyl(5R,6S)-7-oxo-3-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.In the same manner as step b) of example 17, by using this compound,there was obtained sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(54.4 mg).

¹H NMR (400 MHz, D₂O) δ 1.25 (d, 3H, J=6.4 Hz), 2.95 (dd, 1H, J=17.0 Hz,9.8 Hz), 3.32–3.42 (m, 1H), 3.42–3.47 (m, 1H), 3.77 (s, 2H), 4.17–4.24(m, 2H), 7.47–7.52 (m, 2H), 8.34–8.38 (m, 2H).

Example 47

In the same manner as example 3, by using sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 46, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

LC/MS (EI) 522 (M+1)

Example 48

Step a)

In the same manner as step b) of example 2, by usingbistrimethylsilylamide as an additive and from allyl((2R,3S)-2-[2-(4-{[(ethylamino)carbonyl]amino}phenyl)-2-oxoethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetateprepared by reference example 42, there was obtained allyl(5R,6S)-3-(4-{[(ethylamino)carbonyl]amino}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

LC/MS (EI) 472 (M+1)

Step b)

In the same manner as step b) of example 17, by using the compoundprepare in the above step, there was obtained sodium(5R,6S)-3-(4-{[(ethylamino)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, D₂O) δ 0.98 (t, 3H, J=7.2 Hz), 1.17 (d, 3H, J=6.4 Hz),2.94 (dd, 1H, J=16.9 Hz, 9.8 Hz), 3.06 (q, 2H, J=7.2 Hz), 3.29 (dd, 1H,J=16.9 Hz, 8.5 Hz), 3.32–3.39 (m, 1H), 4.08–4.20 (m,.2H), 7.09–7.15 (m,2H), 7.16–7.22 (m,.2H).

Example 49

In the same manner as example 3, from sodium(5R,6S)-3-(4-{[(ethylamino)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 48, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(4-{[(ethylamino)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.10–1.19 (m, 3H), 1.36 (d, 3H,J=6.3 Hz), 3.12–3.38 (m, 5H), 4.11–4.28 (m, 2H), 4.92 (brs, 1H), 5.77(d, 1H, J=5.5 Hz), 5.87 (d, 1H, J=5.5 Hz), 6.51 (s, 1H), 7.20–7.35 (m,4H).

Example 50

Step a)

In the same manner as step b) of example 2, from allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}phenyl)-2-oxoethyl]-3-((1R)-1-[(trimethylsilyl)oxy]ethyl}-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetateprepared by reference example 44, there was obtained allyl(5R,6S)-3-(3-{[(allyloxy)carbonyl]amino}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 1.29 (d, 3H, J=6.1 Hz),3.16–3.28 (m, 3H), 4.17–4.25 (m, 2H), 4.57–4.78 (m, 4H), 5.13–5.44 (m,4H), 5.80–6.06 (m, 2H), 6.65 (brs, 1H), 7.03–7.09 (m, 1H), 7.24–7.31 (m,2H), 7.47(brs, 1H).

Step b)

Allyl(5R,6S)-3-(3-{[(allyloxy)carbonyl]amino}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylatewas subjected to detrimethylsilyl etherification in the same manner asstep b) of example 17 to give allyl(5R,6S)-3-(3-{[(allyloxy)carbonyl]amino}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (d, 3H, J=6.3 Hz), 3.13–3.38 (m, 3H),4.19–4.35 (m, 2H), 4.54–4.77 (m, 4H), 5.12–5.42 (m, 4H), 5.74–6.04 (m,2H), 6.75 (brs, 1H), 7.02–7.09 (m, 1H), 7.24–7.32 (m, 2H), 7.47 (brs,1H).

Step c)

In the same manner as step b) of example 16, from the compound preparedin the above step, there was obtained sodium(5R,6S)-3-(3-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, D₂O) δ 1.19 (d, 3H, J=6.4 Hz), 2.94 (dd, 1H, J=17.0 Hz,9.8 Hz), 3.28 (dd, 1H, J=17.0 Hz, 8.5 Hz), 3.35–3.42 (m, 1H), 4.10–4.20(m, 2H), 6.62–6.73 (m, 3H), 7.03–7.11 (m, 1H).

Example 51

In the same manner as example 3, from sodium(5R,6S)-3-(3-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 50, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(3-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.36 (d, 3H, J=6.3 Hz),3.12–3.28 (m, 3H), 4.20–4.31 (m, 2H), 5.72–5.78 (m, 1H), 5.79–5.84 (m,1H), 6.62–6.73 (m, 3H), 7.07–7.16 (m, 1H).

Example 52

In the same manner as example 3, from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 16, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (s, 9H), 1.33 (d, 3H, J=6.3 Hz), 2.75 (s,3H), 3.20–3.28 (m, 2H), 4.13–4.27 (m, 2H), 4.30–4.38 (m, 2H), 5.70 (d,1H, J=5.6 Hz), 5.79 (d, 1H, J=5.6 Hz), 7.15–7.17 (m, 1H), 7.19–7.30 (m,3H).

Example 53

Step a)

In the same manner as reference example 11, from allyl{(2R,3S)-2-{2-[3-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by reference example 6, there was obtained allyl{(2R,3S)-2-[2-(3-{[(aminocarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step b)

In the same manner as step a) of example 2, by using the compoundprepared in the above step, there was obtained allyl{(2R,3S)-2-[2-(3-{[(aminocarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-({trimethylsilyl}oxy)ethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.This product was used in the next step without further purification.

Step c)

In the same manner as step b) of example 2, by using the compoundprepared in the above step, there was obtained allyl(5R,6S)-3-(3-{[(aminocarbonyl)amino]methyl}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.The product was further treated in the same manner as step b) of example8 to give sodium(5R,6S)-3-(3-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, DMSO-d6) δ 1.09 (d, 3H, J=6.3 Hz), 2.78 (dd, 1H, J=9.8,15.6 Hz), 3.01 (dd, 1H, J=8.5, 15.6 Hz), 3.07 (dd, 1H, J=2.8, 6.5 Hz),3.80–3.88 (m, 1H), 3.91–3.96 (m, 1H), 4.03, (d, 2H, J=5.9 Hz), 4.93 (d,1H, J=5.0 Hz), 6.32 (t, 1H, J=5.9 Hz), 6.92 (br.d, 1H, J=7.7 Hz), 7.07(br.t, 1H, J=7.7 Hz), 7.19 (br.s, 1H), 7.33 (br.d, 1H, J=8.0 Hz). IR(ATR) 3338(br), 2972, 1743, 1649, 1570, 1489, 1389, 1340, 1308, 1246,1223, 1132, 1092, 1039, 999, 978, 951, 887, 783, 696 cm⁻¹.

Example 54

In the same manner as example 3, from sodium(5R,6S)-3-(3-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 53, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(3-{[(aminocarbonyl)amino]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CD₃CN) δ 1.14 (s, 9H), 1.31 (d, 3H, J=6.3 Hz), 3.12(dd, 1H, J=18.5, 9.9 Hz), 3.20–3.28 (m, 2H), 4.09–4.25 (m, 2H), 4.31(br. s, 2H), 5.69 (d, 1H, J=5.6 Hz), 5.79 (d, 1H, J=5.6 Hz), 5.95 (br.s, 1H), 7.16–7.18 (m, 1H), 7.23–7.28 (m, 3H).

Example 55

Step a)

To allyl{(2R,3S)-2-{12-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(3.05 g) prepared by reference example 9 and a solution of triethylamine(1.26 ml) in THF (45 ml) was added at room temperature a suspension ofnicotinoyl chloride hydrochloride (1.19 g) in pyridine (10 mL), and themixture was stirred for 10 minutes. Thereto was added ethyl acetate (100ml) and the mixture was washed with a saturated aqueous sodium chloridesolution (100 ml respectively, three times), dried over sodium sulfateand filtered. The solvent was removed under reduced pressure and theresidue was purified by column chromatography (SiO₂ 150 g,chloroform/methanol=97:3˜91:9) to give allyl{(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-[2-oxo-2-(4-{[(pyridin-3-ylcarbonyl)amino]methyl}phenyl)ethyl]azetidin-1-yl}(triphenylphosphoranilidene)acetate.

Step b)

In the same manner as in step a) of example 2, by using the compoundprepared in the above step, there was obtained allyl((3S,4R)-2-oxo-4-[2-oxo-2-(4-{[(pyridin-3-ylcarbonyl)amino]methyl]}phenyl)ethyl]-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranylidene)acetate.This product was used in the next step without further purification.

Step c)

In the same manner as step b) of example 2, by using a compound preparedin the above step, there was obtained allyl(5R,6S)-7-oxo-3-(4-{[(pyridin-3-yl-carbonyl)amino]methyl}phenyl)-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.The product was further treated in the same manner as step b) of example8 to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(4-{[(pyridin-3-yl-carbonyl)amino]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, DMSO-d6) δ 1.14 (d, 3H, J=6.3 Hz), 2.86 (dd, 1H,J=15.7, 9.9 Hz), 3.08 (dd, 1H, J=15.7, 8.5 Hz), 3.13 (dd, 1H, J=6.6, 2.8Hz), 3.90 (br, 1H), 4.00 (td, 1H, J=8.9, 2.7 Hz), 4.44 (d, 2H, J=5.9Hz), 5.01 (br. d, 1H, J=3.7 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.42 (d, 2H,J=8.4 Hz), 7.49 (ddd, 1H, J=0.8, 4.8, 7.9 Hz), 8.22 (td, 1H, J=2.0, 7.9Hz), 8.69 (dd, 1H, J=1.7, 4.8 Hz), 9.03 (dd, 1H, J=0.8, 2.2 Hz), 9.31(t, 1H, J=5.9 Hz). IR (ATR) 3267, 1747, 1643, 1589, 1547, 1477, 1392,1308, 1246, 1223, 1158, 1130, 1092, 1030, 987, 945, 879, 802, 787, 706,675, 621 cm⁻¹.

Example 56

In the same manner as example 3, from sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(4-{[(pyridin-3-ylcarbonyl)amino]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateprepared by example 55, there was obtained[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(4-{[(pyridin-3-ylcarbonyl)amino]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (s, 3H), 1.37 (d, 3H, J=3.6 Hz), 3.21(dd, 1H, J=9.9 Hz, 18.5 Hz), 3.27 (dd, 1H, J=2.8 Hz, 6.6 Hz), 3.31 (dd,1H, J=8.9 Hz, 18.5 Hz), 4.21–4.37 (m, 2H), 4.67 (d, 2H, J=5.5 Hz), 5.73(d, 1H, J=5.5 Hz), 5.81 (d, 1H, J=5.5 Hz), 6.74 (br. t, 1H), 7.30–7.36(m, 4H), 7.40 (ddd, 1H, J=0.7 Hz, 4.8 Hz, 8.0 Hz), 8.18 (dt, 1H, J=8.0Hz, 2.0 Hz), 8.73 (dd, 1H, J=1.7 Hz, 4.8 Hz), 9.02 (d, 1H, J=1.7 Hz).

Reference Example 1

To a solution of(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate(5.75 g) and a solution oftert-butyl(dimethyl)(3-{1-[(trimethylsilyl)oxy]vinyl}phenoxy)silane(about 20 mmol) in dry dichloromethane (36 ml) was added at roomtemperature zinc iodide (6.38 g, 20 mmol) and the mixture was reacted atthe same temperature overnight. The reaction mixture was poured into icewater, diluted and extracted with ethyl acetate. The mixture wasseparated by a separating funnel. The organic layer was washed with asaturated aqueous sodium chloride solution (twice), an aqueous sodiumhydrogencarbonate solution, and a saturated aqueous sodium chloridesolution in the order, and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure and the residue wascrystallized from hexane, collected by filtration, washed and driedunder reduced pressure to give(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-oxoethyl]azetidin-2-one(7.161 g).

¹H NMR (400 MHz, CDCl₃) δ 0.078 (6H, s), 0.084 (6H, s), 0.22 (9H, s),0.88 (9H, s), 1.00 (9H, s), 1.25 (3H, d, J=6.2 Hz), 2.89 (1H, dd, J=2.3Hz, 5.4 Hz), 3.07–3.18 (1H, m), 3.37–3.49 (1H, m), 4.07–4.16 (1H, m),4.17–4.28 (1H, m), 6.11 (1H, s), 7.03–7.12 (1H, m), 7.30–7.44 (2H, m),7.52 (1H, d, J=7.8 Hz).

Reference Example 2

Step a)

A solution of p-nitrobenzyl glyoxalate monohydrate (2.73 g) in toluene(100 ml) was subjected to azeotropic dehydration under refluxing. Aftercooled to room temperature once, therein was dissolved(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-oxoethyl]azetidin-2-one(4.78 g) and the solution was azeotropicly dehydrated under refluxing.After disappearance of a starting material, the solvent was removedunder reduced pressure. The residue was dried and dissolved in THF (40ml). Thereto was added 2,6-lutidine (1.61 g) and the mixture was cooledat −20˜−30° C. At the same temperature thereto was dropped thionylchloride (1.78 g). After filtration of insoluble materials and washingwith dry THF, the filtrate was concentrated in a bath at less than 35°C. under reduced pressure. The residue was dissolved in dry 1,4-dioxane(40 ml) and thereto were added triphenylphosphine (5.77 g) and2,6-lutidine (2.36 g). The mixture was stirred in a bath at 50° C. fortwo hours. After the mixture was cooled to room temperature, theretowere added ethyl acetate and a cold saturated aqueous sodium chloridesolution. The mixture was extract and separated with a separatingfunnel. The organic layer was washed with a cold aqueous potassiumhydrogensulfate solution (twice), a cold saturated aqueous sodiumchloride solution (twice), a cold aqueous sodium hydrogencarbonatesolution and a cold saturated aqueous sodium chloride solution in theorder, and dried over anhydrous sodium sulfate. After the solvent wasremoved under reduced pressure, the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give 4-nitrobenzyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(7.310 g).

Step b)

To a solution of 4-nitrobenzyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.89 g) and acetic acid (2.40 g) in THF (20 ml) was dropped at roomtemperature 1M tetrabutylammonium fluoride in THF (12 ml) and then, themixture was stirred for 7.5 hours in a bath at 50° C. The reactionmixture was cooled to room temperature, and thereto were added ethylacetate and a cold saturated aqueous sodium chloride solution. Themixture was extracted and separated by a separating funnel. The organiclayer was washed with a cold aqueous sodium hydrogencarbonate solutionand a cold (three times) in the order, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas crystallized from diethyl ether, filtered, washed and dried underreduced pressure to give 4-nitrobenzyl{(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-[2-(3-hydroxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.168 g).

IR (KBr) 3423 (broad), 1727, 1604, 1256, 750, 720, 692 cm⁻¹.

Reference Example 3

In the same manner as reference example 1, by usingtert-butyl(dimethyl)[(3-{1-[(trimethylsilyl)oxy]vinyl}benzyl)oxy]silaneinstead of tert-butyl(dimethyl) (3-{1-[(trimethylsilyl)oxy]vinyl}phenoxy)silane, there was obtained(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxoethyl}azetidin-2-one.

¹H NMR (400 MHz, CDCl₃) δ 0.08 (s, 6H), 0.12 (s, 6H), 0.87 (s, 9H), 0.95(s, 9H), 1.25 (d, 3H, J=5.6 Hz), 2.87–2.89 (m, 1H), 3.13–3.20 (m, 1H),3.46 (dd, 1H, J=17.7, 3.0 Hz), 4.21–4.24 (m, 1H), 4.80 (s, 2H), 6.11 (s,1H), 7.46 (t, 1H, J=7.7 Hz), 7.57 (d, 1H, J=7.7Hz), 7.82 (d, 1H,J=7.7Hz), 7.90 (s, 1H).

Reference Example 4

In the same manner as reference example 2, by using allyl glyoxalatemonohydrate instead of p-nitrobenzyl glyoxalate monohydrate, there wasobtained allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[3-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate.

IR (KBr) 3324 (broad), 1767, 1738, 1671, 1439, 1373, 1245, 1124, 1107,1084, 692 cm⁻¹.

Reference Example 5

In the same manner as reference example 1, by using tert-butyl(3-{1-[(trimethylsilyl)oxy]vinyl}benzyl) carbamate instead oftert-butyl(dimethyl)(3-{1-[(trimethylsilyl)oxy]vinyl}phenoxy)silane,there was obtainedtert-butyl-3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}benzylcarbamate.

¹H NMR (400 MHz, CDCl₃) δ 0.08 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 1.25(d, 3H, J=6.3 Hz), 1.47 (s, 9H), 2.89 (dd, 1H, J=2.2 Hz, 5.3 Hz), 3.17(dd, 1H, J=10.1 Hz, 17.8 Hz), 3.46 (dd, 1H, J=3.0 Hz, 17.8 Hz),4.09–4.16 (m, 1H), 4.19–4.27 (m, 1H), 4.38 (d, 2H, J=6.2 Hz), 4.96(broad s, 1H), 6.14 (broad s, 1H), 7.43–7.48 (m, 1H), 7.52–7.55 (m, 1H),7.82–7.87 (m, 2H).

Reference Example 6

Step a)

In the same manner as reference example 2, by usingtert-butyl-(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}benzylcarbamate (4.75 g) prepared by reference example 5 and by using allylglyoxalate monohydrate instead of p-nitrobenzyl glyoxalate monohydrate,there was obtained allyl[(2R,3S)-2-[2-(3-{[(tert-butoxycabonyl)amino]methyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

Step b)

The compound (1.0 g) prepared in the above step a) was dissolved in anaqueous 70% trifluoroacetic acid solution and the solution was stirredat room temperature for 1 hour. Thereto was added 0.1M phosphate buffer(pH6.86, 10 ml) and the solution was extracted with ethyl acetate (3×10ml). The organic layers were combined, dried and filtered. The solventwas removed under reduced pressure to give allyl{(2R,3S)-2-{2-[3-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.

Reference Example 7

To a solution of allyl{(2R,3S)-2-{2-[3-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(0.7 g) prepared by reference example 6 in THF (2 ml) were added4-nitrophenyl methyl carbamate (196 mg) and N,N-diisopropylethylamine(0.17 ml). The mixture was stirred for 1 hour and additional4-nitrophenyl methyl carbamate (50 mg) and N,N-diisopropylethylamine(0.17 ml) were added thereto. The mixture was stirred for 1 hour.Thereto was added 0.1M phosphate buffer (pH6.86, 10 ml) and the mixturewas extracted with ethyl acetate (3×10 ml), dried over sodium sulfateand filtered. The solvent was removed under reduced pressure. Theresidue, triethylamine (0.17 ml) and 4-dimethylaminopyridine (7.3 mg)were dissolved in THF (2 mL) and thereto was added at 0° C. allylchloroformate (0.095 ml). The mixture was reacted at room temperaturefor 14 hours. Thereto was added 0.1M phosphate buffer (pH6.86, 10 ml)and the mixture was extracted with ethyl acetate (3×10 ml), dried oversodium sulfate and filtered. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol=100:0˜10:1) to give allyl((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[3-({[(methylamino)carbonyl]amino}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetateas a pale yellow oil (94 mg).

Reference Example 8

In the same manner as reference example 1, by usingtert-butyl(4-{1-[(trimethylsilyl)oxy]vinyl}benzyl) carbamate instead oftert-butyl(dimethyl)(3-{1-[(trimethylsilyl)oxy]vinyl}phenoxy)silane,there was obtainedtert-butyl-4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}benzylcarbamate (5.53 g).

¹H NMR (400 MHz, CDCl₃) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.24(d, 3H, J=6.2 Hz), 1.45 (br, 9H), 2.87 (dd, 1H, J=2.3 Hz, 5.4 Hz), 3.14(dd, 1H, J=10.2 Hz, 17.7 Hz), 3.43 (dd, 1H, J=3.0 Hz, 17.7 Hz),4.08–4.12 (m, 1H), 4.18–4.24 (m, 1H), 4.37 (d, 2H, J=5.9 Hz), 4.95(broad s, 1H), 6.11 (broad s, 1H), 7.37–7.39 (m, 2H), 7.89–7.91 (m, 2H).

Reference Example 9

Step a)

In the same manner as reference example 2, by usingtert-butyl-4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}benzyl carbamate (18.7 g)prepared by reference example 8, and using allyl glyoxalate monohydrateinstead of p-nitrobenzyl glyoxalate monohydrate, there was obtainedallyl[(2R,3S)-2-[2-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

Step b)

The compound (2.0 g) prepared in Step a) was dissolved in an aqueous 70%trifluoroacetic acid solution and the solution was reacted overnight.The solution was neutralized with an aqueous saturated sodiumhydrogencarbonate solution (10 ml) and sodium hydrogencarbonate, and themixture was extracted with chloroform (3×20 ml). The organic layers werecombined, dried over magnesium sulfate and filtered. The solvent wasremoved under reduced pressure to give allyl{(2R,3S)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.

Reference Example 10

To a solution of allyl{(2R,3S)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.8 g) prepared by reference example 9 in THF (10 ml) were added4-nitrophenyl methyl carbamate (565 mg) and triethylamine (0.34 ml), andthe mixture was reacted overnight. Then, thereto were addedtriethylamine (0.34 ml), triethylamine (0.68 ml) andchlorotrimethylsilane (0.74 ml), and the mixture was stirred for 3hours. Thereto was added 0.1M phosphate buffer (pH6.86, 30 ml) and themixture was extracted with ethyl acetate (3×20 ml), dried over,magnesium sulfate and filtered. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (chloroform/methanol=10:1) to give allyl((2R,3S)-2-{2-[4-({[(methylamino)carbonyl]amino}methyl)phenyl]-2-oxoethyl}-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(0.74 g).

Reference Example 11

To a solution of allyl{(2R,3S)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.7 g) prepared by reference example 9 in THF (5 ml) was addedtrimethylsilylisocyanate (0.57 ml) and the solution was stirred for 2hours. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography(chloroform/methanol=95:5˜100:20) to give allyl{(2R,3S)-2-[2-(4-{[(aminocarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate.

Reference Example 12

Step a)

Starting from allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetatein the same manner as step b) of reference example 2 except for reactingunder ice cooling, there was obtained allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate.

Step b)

Allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(900 mg) and pyridine (a catalytic amount) were dissolved indichloromethane (7.5 ml), and thereto was added trichloroacetylisocyanate (345 mg). The mixture was stirred for 1 hour under icecooling. The reaction mixture was poured into ice water, and the mixturewas diluted, extracted with ethyl acetate and separated by a separatingfunnel. The organic layer was washed with an aqueous 5% potassiumhydrogensulfate solution, water and a saturated aqueous sodium chloridesolution in the order, and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure. The residue was dissolved inacetonitrile (21 ml) and thereto was added under ice coolingborontrifluoride-diethyl ether complex (519 mg). The mixture was stirredfor 15 minutes. The reaction mixture was poured into ice water, diluted,extracted with ethyl acetate, and separated with a separating funnel.The organic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure. 92/100 (by weight %) of the residue weredissolved in dichloromethane (6 ml) under ice cooling and thereto wereadded 4-dimethylaminopyridine (410 mg) and allyl chloroformate (270 mg).The mixture was stirred for 3 hours. The reaction mixture was pouredinto ice water and diluted with ethyl acetate. After the aqueous layerwas acidified with an aqueous 5% potassium hydrogensulfate solution, themixture was extracted and separated with a separating funnel. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, an aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution in the order, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure. Theresidue was dissolved in methanol (30 ml), and thereto was added asilica gel (10.5 g). The mixture was left to stand at room temperaturefor 3 days. To the reaction mixture was added chloroform (150 ml) andsilica gel was filtered off. The filtrate was washed withchloroform/methanol. The filtrate was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate, followed by ethyl acetate/acetone)to give allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(409 mg).

Reference Example 13

Step a)

A mixture of 5-acetylthiophene-2-carboxylic acid (41.44 g),p-toluenesulfonic acid monohydrate (926 mg), ethylene glycol (226 g) andtoluene (500 ml) was refluxed under heating for 13 hours and subjectedto azeotropic dehydration. The reaction mixture was washed with asaturated aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give a brawnsolution. This product was dissolved in THF (500 ml) and the solutionwas gradually dropped to a mixture of lithium aluminum hydride (19.22 g)and THF (750 ml) under ice cooling. Two hours later, thereto was added a10% aqueous sodium hydroxide solution (1000 ml). After the removal ofinsoluble materials, the filtrate was extracted with ethyl acetate. Theorganic layer was washed with water (twice) and was dried over anhydroussodium sulfate. The solvent was removed under reduced pressure to give[5-(2-methyl-1,3-dioxolan-2-yl)thien-2-yl]methanol. This product wasused in the next step without purification.

Step b)

To a solution of [5-(2-methyl-1,3-dioxolan-2-yl)thien-2-yl]methanolprepared in the above step in THF (240 ml) was added 1N hydrochloricacid (48 ml) and the mixture was stirred for 2 hours at roomtemperature. Thereto was added sodium hydrogencarbonate (4.04 g) and themixture was extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 1-[5-(hydroxymethyl)thien-2-yl]ethanone. This product was usedin the next step without purification.

Step c)

To a solution of 1-[5-(hydroxymethyl)thien-2-yl]ethanone prepared in theabove step in DMF (84 ml) was added imidazole (27.11 g) and thereto wasdropped under ice cooling tert-butyldimethylchlorosilane (30.01 g).Thirty minutes later, thereto was added ice water (250 ml) and themixture was extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]ethanone (46.53g).

¹H NMR (400 MHz, CDCl₃) δ 0.11 (s, 6H), 0.93 (s, 9H), 2.53 (s, 3H), 4.87(d, 2H, J=0.9 Hz), 6.92 (d, 1H, J=3.8 Hz), 7.56 (d, 1H, J=3.8 Hz).

Step d)

To a solution of1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]ethanone (19.75g) in THF (200 ml) was added triethylamine (11.08 g). To the mixture wasdropped at −78° C. 1N-lithium hexamethyldisilazane (87.63 ml), followedby chlorotrimethylsilane (9.52 g) and the mixture was stirred for 1hour. Thereto was added hexane (200 ml) and the mixture was poured intowater (300 ml) and extracted with hexane. The organic layer was washedwith a saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto givetert-butyl(dimethyl)[(5-{1-[(trimethylsilyl)oxy]vinyl}thien-2-yl)methoxy]silane.This product was used in the next step without purification.

Step e)

In the same manner as reference example 3, fromtert-butyl(dimethyl)[(5-{1-[(trimethylsilyl)oxy]vinyl}thien-2-yl)methoxy]silaneprepared in the above step and(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (20.99 g), there was obtained(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]-2-oxoethyl}azetidin-2-one (10.32 g).

¹H NMR (400 MHz, CDCl₃) δ 0.069 (s, 3H), 0.075 (s, 3H), 0.12 (s, 3H+3H),0.87 (s, 9H), 0.94 (s, 9H), 1.24 (d, 3H, J=6.2 Hz), 2.87 (dd, 1H, J=5.4Hz, 2.2 Hz), 3.07 (dd, 1H, J=16.9 Hz, 10.1 Hz), 3.34 (dd, 1H, J=6.9 Hz,3.3 Hz), 4.07–4.11 (m, 1H), 4.18–4.24 (m, 1H), 4.89 (d, 2H, J=0.7Hz),6.08 (s, 1H), 6.94 (s, 1H, J=3.9 Hz), 7.58 (d, 1H, J=3.9 Hz).

Reference Example 14

Step a)

In the same manner as reference example 4, from(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]-2-oxoethyl}azetidin-2-one(4.92 g) prepared by reference example 12, there was obtained allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(2.90 g).

LC-MS (m/e): 856 (M+1).

Step b)

To a solution of allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(2.90 g) prepared in the above step in acetonitrile (58 ml) was added at0° C. borontrifluoride diethyl ether (2.89 g) and the mixture wasstirred at room temperature for 24 hours. Thereto was added 0.1Mphosphate buffer (pH6.86, 87 ml) and the solution was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium chloride solution and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[5-hydroxymethyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate.This product was used in the next step without purification.

Step c)

To a solution of allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[5-(hydroxymethyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetateprepared in the above step in dichloromethane (30 ml) was addedN,N-dimethylaminopyridine (2.98 g) and to the mixture was added at underice cooling allyl chloroformate (2.45 g). The mixture was stirred atroom temperature overnight and diluted with chloroform and a coldaqueous potassium hydrogensulfate, and separated with a separatingfunnel. The organic layer was washed successively with a saturatedaqueous sodium chloride solution, an aqueous sodium hydrogencarbonatesolution and a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give allyl((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[5-({[(allyloxy)carbonyl]oxy}methyl)thien-2-yl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(2. 56 g).

Reference Example 15

In the same manner as reference example 1, by using triethyl[2-(3-{1n-[(trimethylsilyl)oxy]vinyl}phenyl)ethoxy]silane instead oftert-butyl(dimethyl)(3-(1-[(trimethylsilyl)oxy]vinyl}phenoxy)silane,there was obtained(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[3-(2-hydroxyethyl)phenyl]-2-oxoethyl}azetidin-2-one.

¹H NMR (400 MHz, CDCl₃) δ 0.08 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 1.26(d, 3H, J=6.2 Hz), 1.46 (br. t, 1H, J=4.8 Hz), 2.89 (dd, 1H, J=2.3 Hz,5.4 Hz), 2.95 (t, 2H, J=6.5 Hz), 3.18 (dd, 1H, J=10.2 Hz, 17.7 Hz), 3.46(dd, 1H, J=3.0 Hz, 17.7 Hz), 3.91 (broad dt, 2H, J=4.8 Hz, 6.5 Hz),4.10–4.14 (m, 1H), 4.20–4.26 (m, 1H), 6.13 (broad s, 1H), 7.42–7.52 (m,2H), 7.80–7.83 (m, 2H).

Reference Example 16

(3S,4R)-3-((1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[3-(2-hydroxyethyl)phenyl]-2-oxoethyl}azetidin-2-one(3.0 g) prepared by reference example 15 and ruthenium trichloride (79mg) were dissolved in acetone (77 ml) and to the solution was added atroom temperature a solution of sodium periodate (3.3 g) in water (40ml). The solution was stirred for 30 minutes. Further, a solution ofsodium periodate (0.66 g) in water (4 ml) was added thereto and thesolution was stirred for 3 hours. After removal of insoluble materialsby filtration with celite, acetone was removed under reduced pressure.To the aqueous layer (about 50 ml) was added a saturated aqueous sodiumchloride solution (100 ml) and the mixture was extracted with ethylacetate (3×50 ml). The organic layers were combined, dried overmagnesium sulfate and filtered. The solvent was removed under reducedpressure to give(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid (2.72 g).

¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.24(d, 3H, J=6.2 Hz), 2.91 (dd, 1 H, J=2.2, 5.2 Hz), 3.19 (dd, 1H, J=10.0Hz, 17.7 Hz), 3.43 (dd, 1H, J=3.1 Hz, 17.7 Hz), 3.72 (s, 2H), 4.11–4.19(m, 1H), 4.20–4.26 (m, 1H), 6.39 (broad s, 1H), 7.44–7.53 (m, 2H),7.84–7.88 (m, 2H).

Reference Example 17

To a solution of(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid (2.62 g) prepared in reference example 16, 4-dimethylaminopyridine(78 mg) and 2.0M methylamine/THF (3.3 ml) in dichloromethane (25 ml) wasadded at 0° C. 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride(1.24 g) and the mixture was stirred for 6 hours. Further,1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (0.13 g) and2.0M methylamine/THF (0.33 ml) were added thereto and the mixture wasreacted overnight. To the mixture was added an aqueous saturatedammonium chloride solution (50 ml) and the mixture was extracted withethyl acetate.(100 ml). The organic layer was washed with a saturatedaqueous sodium chloride solution (2×50 ml), dried over magnesium sulfateand filtered. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography(chloroform/methanol) to give2-(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)-N-methylacetamide(1.96 g).

¹H NMR (300 MHz, CDCl₃) δ 0.08 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9), 1.26(d, 3H, J=6.3 Hz), 2.79 (d, 3H, J=5.0 Hz), 2.89 (dd, 1H, J=2.3, 5.4 Hz),3.17 (dd, 1H, J=10.1 Hz, 17.8 Hz), 3.47 (dd, 1H, J=2.9 Hz, 17.8 Hz),3.62 (s, 2H), 4.12–4.16 (m, 1H), 4.20–4.28 (m, 1H), 5.62 (broad s, 1H),6.33 (broad s, 1H), 7.45–7.50 (m, 1H), 7.54–7.57 (m, 1H), 7.84–7.87 (m,2H).

Reference Example 18

By using2-(3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)-N-methylactetamide(1.96 g) prepared by reference example 17 and by using allyl glyoxalatemonohydrate instead of p-nitrobenzyl glyoxalate monohydrate in the samemanner as step a) of reference example 2, there was obtained allyl[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(2-{3-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(2.73 g).

Reference Example 19

By usingtert-butyl(dimethyl)[2-(4-{1-[(trimethylsilyl)oxy]vinyl}phenyl)ethoxy]silanein stead of tert-butyl(dimethyl) (3-{1-[(trimethylsilyl)oxy]vinyl}phenoxy) silane in the same manner asreference example 1, there was obtained(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-oxoethyl}azetidin-2-one(16.3 g).

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 6H), 0.11 (s, 3H), 0.12 (s, 3H), 0.89(s, 9H), 0.91 (s, 9H), 1.29 (d, 3H, J=6.0 Hz), 2.87–2.94 (m, 3H), 3.19(dd, 1H, J=10.2 Hz, 17.6 Hz), 3.49 (dd, 1H, J=3.0 Hz, 17.6 Hz),3.85–3.89 (m, 2H), 4.13–4.18 (m, 1H), 4.24–4.28 (m, 1H), 6.16 (broad s,1H), 7.32–7.38 (m, 2H), 7.89–7.93 (m, 2H).

Reference Example 20

There was obtained allyl4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamate in the same manner as reference example 1.

¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 6H), 0.87 (s, 9H), 1.24 (d, 3H, J=6.2Hz), 2.86–2.89 (m, 1H), 3.08–3.16 (m, 1H), 3.39–3.45 (m, 1H), 4.09–4.13(m, 1H), 4.18–4.25 (m, 1H), 4.69 (d, 2H, J=5.8 Hz),5.25–5.42 (m, 2H),5.92–6.01 (m, 1H), 6.15 (s, 1H), 7.52 (d, 2H, J=8.7 Hz), 7.91 (d, 2H,J=8.7 Hz)

Reference Example 21

Step a)

By using allyl4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamatein the same manner as step a) of reference example 9, there was obtainedallyl[(2R,3S)-2-[2-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 805 (M+1)

Step b)

There was obtained allyl[(2R,3S)-2-[2-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetatein the same manner as step b) of reference example 9.

LC/MS (EI) 691 (M+1)

Reference Example 22

Step a)

In the same manner as step a) of reference example 9, by using(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[4-(2-{tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-oxoethyl}azetidin-2-one,there was obtained allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate.

LC/MS (EI) 865 (M+1)

Reference Example 23

Step a)

To a solution of allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(25.7 g) in THF (300 ml) were added acetic acid (2.95 ml) and a solutionof 1M tetrabutylammonium fluoride/THF (26 ml), and the mixture wasstirred for 24 hours. The solution was diluted with ethyl acetate andwashed with a saturated aqueous sodium chloride solution. The organiclayer was dried and concentrated, and the residue was purified by silicagel column chromatography (ethyl acetate) to give allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[4-(2-hydroxyethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(15.3 g).

LC/MS (EI) 750 (M+1)

Step b)

To a solution of the compound (3 g) prepared in the above step inacetone (30 ml) was added Jones reagent (3 ml). Thirty minutes later,the mixture was diluted with ethyl acetate and washed with water. Theorganic layer was dried and concentrated to give(4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid (3.17 g).

LC/MS (EI) 764 (M+1)

Step c)

To a solution of the compound (3.17 g) prepared in the above step indichloromethane (30 ml) were added N,N-dimethylformamide (0.04 ml) andthionyl chloride (0.37 ml). One and a half hours later, the reactionmixture was dropped to a mixture of an aqueous 40% methylamine solution(30 ml) and dichloromethane (101 ml). The reaction mixture was dilutedwith ethyl acetate and washed with an aqueous sodium hydrogencarbonatesolution and a saturated aqueous sodium chloride solution. The organiclayer was dried and concentrated to give allyl[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(2-{4-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 777 (M+1)

Step d)

A solution of the compound prepared in the above step in an aqueous 70%trifluoroacetic acid (45 ml) was stirred for 1 hour. After concentratingthe reaction solution, the mixture was diluted with ethyl acetate andwashed with a saturated aqueous sodium hydrogencarbonate solution and asaturated aqueous sodium chloride solution. The organic layer was dried,concentrated and the residue was purified by silica gel columnchromatography (ethyl acetate: ethanol=5:1) to give allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(1.82 g).

LC/MS (EI) 663 (M+1)

Reference Example 24

Step a)

In the same manner as step c) of reference example 23, from(4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid, there was obtained allyl[(2R,3S)-2-{2-[4-(2-amino-2-oxoethyl)phenyl]-2-oxoethyl}-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 763 (M+1)

Step b)

In the same manner as step d) of reference example 23, from allyl[(2R,3S)-2-{2-[4-(2-amino-2-oxoethyl)phenyl]-2-oxoethyl}-3-((1R)-1-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate,there was obtained allyl[(2R,3S)-2-{2-[4-(2-amino-2-oxoethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 649 (M+1)

Reference Example 25

In the same manner as step d) of reference example 23, from allyl[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(2-{3-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate,there was obtained allyl[(2R,3S)-3-f[(1R)-1-hydroxyethyl]-2-(2-{3-[2-(methylamino)-2-oxoethyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 663 (M+1)

Reference Example 26

To a solution of allyl{(2R,3S)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.6 g) prepared by reference example 9 and triethylamine (0.35 ml) inTHF (13 ml) was added at 0° C. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-nitrophenylcarbonate (0.40 g) and the mixture was stirred for 2 hours.Further, thereto were added (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-nitrophenylcarbonate (0.80 g) and triethylamine (0.35 ml), and themixture was reacted at room temperature for 34 hours. To the reactionmixture was added a saturated aqueous sodium chloride solution (50 ml)and the mixture was extracted with ethyl acetate (3×50 ml). The organiclayers were combined and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (chloroform/methanol=10:1) to giveallyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[({[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl}amino)methyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(0.52 g).

Reference Example 27

Step a)

In the same manner as step a) of reference example 12, from allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(1.978 g), there was obtained allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(1.358 g, pale yellow amorphous). Allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenyIphosphoranilidene)acetate(0.308 g), the starting material was recovered.

Allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate

IR(ATR) 2953, 2927, 2885, 2856, 1743, 1682, 1620, 1437, 1371, 1252,1103, 833, 775, 690 cm⁻¹. LC/MS (EI) 851 (M+1)+.

Allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate

IR(ATR) 3417(broad), 2951, 2927, 1740, 1678, 1620, 1439, 1373, 1242,1103, 833, 775, 752, 717, 690 cm⁻¹. LC/MS (EI) 737 (M+1)+.

Step b)

To a solution of allyl((2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-{2-[3-(hydroxymethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(1.341g) and pyridine (a catalytic amount) in dichloromethane (11 ml) wasadded trichloroacetyl isocyanate (514 mg) and the mixture was stirredunder ice cooling for 1 hour. The reaction mixture was poured into icewater, diluted, extracted with ethyl acetate and separated by aseparating funnel. The organic layer was washed with a cold aqueous 5%potassium hydrogensulfate solution, a saturated aqueous sodium chloridesolution, a saturated aqueous sodium hydrogencarbonate solution and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive allyl[(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-4-(2-oxo-2-{3-[({[(trichloroacetyl)amino]carbonyl}oxy)methyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(pale yellow amorphous).

LC/MS (EI) 925.5 (M+1)+. IR(ATR) 2951, 2931, 1797, 1724, 1605, 1439,1246, 1169, 1103, 829, 690 cm⁻¹.

Step c)

Allyl[(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-4-(2-oxo2-{3-[({[(trichloroacetyl)amino]carbonyl}oxy)methyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetateprepared in step b) without purification, was dissolved in acetonitrile(31 ml), and thereto was added under ice cooling borontrifluoride-diethyl ether (568 mg). The mixture was stirred at roomtemperature for 20 hours. The reaction mixture was poured into icewater, diluted, extracted with ethyl acetate and separated by aseparating funnel. The organic layer was washed with a saturated aqueoussodium chloride solution and died over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure to give allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{3-[({[(trichlorocetyl)amino]carbonyl}oxy)methyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(yellowish white amorphous).

LC/MS (EI) 811 (M+1)+. IR(ATR) 3286(broad), 1794, 1767, 1728, 1508,1439, 1246, 1169, 1103, 1045, 999, 825, 748, 690, 667 cm⁻¹.

Step d)

Allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{3-[({[(trichloroacetyl)amino]carbonyl}oxy)methyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetateprepared in the above step c) without purification, was dissolved indichloromethane (15 ml), and thereto were added 4-dimethylaminopyridine(1.00 g) and allyl chloroformate (921 mg). The mixture was stirred for 5days. The reaction mixture was poured into ice water and diluted withchloroform. The aqueous layer was acidified with an aqueous 5% potassiumhydrogensulfate solution, extracted and separated by a separatingfunnel. The organic layer was washed successively with a saturatedaqueous sodium chloride solution, a saturated aqueous sodiumhydrogencarbonate solution and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by silicagel column chromatography (chloroform, followed bychloroform/methanol=100/1˜100/4) to give allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(3-{[(aminocarbonyl)oxy]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(553 mg, yellowish brown oil).

LC/MS (EI) 750 (M+1)+. IR(ATR) 3359(broad), 2974, 2939, 1736, 1616,1250, 1103, 1053, 752, 717, 690 cm⁻¹.

Reference Example 28

Step a)

To a solution of allyl[(2R,3S)-2-[2-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(10.06 g) prepared by step a) of reference example 9 and acetic acid(5.79 g) in THF (30 ml) was dropped 1M tetrabutylammonium fluoride/THF(60 ml). The mixture was heated for 7 hours in a bath at 40° C. andstirred at room temperature for 20 hours. To the reaction solution wereadded ethyl acetate and a cold saturated aqueous sodium chloridesolution and the mixture was extracted and separated by a separatingfunnel. The organic layer was washed successively with a cold aqueoussodium hydrogencarbonate and a cold saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1˜1/2, followed by onlyethyl acetate) to give allyl{(2R,3S)-2-[2-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(7.185 g, brown amorphous).

IR(ATR) 3348(broad), 2978, 1736, 1709, 1682, 1608, 1439, 1365, 1250,1165, 1103, 752, 717, 690 cm⁻¹. LC/MS (EI) 722 (M+1)+.

Step b)

To a solution of the compound (7.17 g) prepared in the above step a) and4-dimethylaminopyridine (3.64 g) in dichloromethane (70 ml) was addedallyl chloroformate (3.36 g) and the mixture was stirred for 5 days. Thereaction solution was poured into ice water and diluted with chloroform.The aqueous layer was acidified with an aqueous 5% potassiumhydrogensulfate solution, extracted and separated by a separatingfunnel. The organic layer was washed successively with a saturatedaqueous sodium chloride solution, a saturated aqueous sodiumhydrogencarbonate solution and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by silicagel column chromatography (hekane/ethyl acetate=2/1˜1/5, followed byonly ethyl acetate and then ethyl acetate/acetone=500/15˜500/20) to giveallyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(5.866 g, yellowish brown amorphous).

IR(ATR) 3329(broad), 2981, 2935, 1740, 1709, 1682, 1608, 1439, 1365,1250, 1165, 1107, 752, 717, 690 cm⁻¹. LC/MS (EI) 806 (M+1)+.

Step c)

To the compound (1.10 g) prepared in the above step b) was added underice cooling trifluoroacetic acid (3 ml) and the mixture was warmed toroom temperature. After the mixture was stirred for 1 hour, thereto wasadded toluene and the solution was concentrated under reduced pressure.The residue was dissolved in chloroform and to the solution was addedunder ice cooling an aqueous sodium hydrogencarbonate solution. Theaqueous layer was extracted three times with chloroform. The organiclayers were combined, washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give allyl((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate(yellow amorphous).

IR(ATR) 1743, 1674, 1142, 1107 cm⁻¹. LC/MS (EI) 706 (M+1)+.

Step d)

In accordance with a method described in the literature (Synthesis,1992, 1058), a total amount of the compound prepared in the above stepc) was dissolved in dichloromethane (20 ml) and thereto was addedN-(diethylcarbamoyl)-N-methoxyformamide (310 mg). After stirred at roomtemperature for 16 hours, the reaction mixture was concentrated underreduced pressure and the residue was dissolved in chloroform. Thesolution was washed with an aqueous sodium hydrogencarbonate solution,and a saturated aqueous sodium chloride solution in the order, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (chloroform, followed by chloroform/methanol=100/1˜100/5)to give allyl[(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-(2-{4-[(formylamino)methyl]phenyl}-2-oxoethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(721 mg, yellow amorphous).

IR(ATR) 3298(broad), 3059, 2935, 1740, 1678, 1608, 1439, 1377, 1450,1103, 752, 717, 690 cm⁻¹. LC/MS (EI) 733 (M+1)+.

Reference Example 29

Allyl{(2R,3S)-3-((1R)-1-{[(allyoxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(1.258 g) prepared by step b) of reference example 28, was treated inthe same manner as step c) of reference example 9xxx1 to give allyl((2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-{2-[4-(aminomethyl)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetateand this product was dissolved in THF (20 ml). Thereto was addedtriethylamine (1.0 ml), followed by methyl chloroformate (151 mg) andthe mixture was stirred for 5 hours. The reaction mixture was pouredinto ice water, extracted with ethyl acetate and separated by aseparating funnel. The organic layer was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=1/1˜1/2,followed with ethyl acetate alone) to give allyl{(2R,3S)-3-((1R)-1-{[(allyloxy)carbonyl]oxy}ethyl)-2-[2-(4-{[(methoxycarbonyl)amino]methyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(801 mg, yellowish white amorphous).

IR(ATR) 3305(broad), 3059, 2942, 1740, 1250, 1103, 752, 717, 690 cm⁻¹.LC/MS (EI) 764 (M+1)+.

Reference Example 30

Step a)

A mixture of 4-acetylphenylisocyanate (20.00 g), t-butyl alcohol (31.00g) and dioxane (60 mL) was heated at 60° C. and thereto was droppedtriethylamine (20.40 g). After stirring for 6 hours, the reactionmixture was poured into ice water, diluted with ethyl acetate, extractedand separated. The organic layer was washed successively with asaturated aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give a paleyellow powder. Thereto was added hexane (100 mL) and the solution wasstirred for 20 minutes, filtered, washed and dried under reducedpressure to give p-(N-tert-butoxycarbonyl)aminoacetophenone (24.61 g).

¹H NMR (400 MHz, CDCl₃) δ 1.47 (s, 9H), 2.56 (s, 3H), 7.42 (d, 2H, J=20Hz), 7.90 (d, 2H, J=20 Hz).

Step b)

A solution of p-(N-t-butoxycarbonyl)aminoacetophenone (23.20 g) preparedin the above step in dichloromethane (116 mL) was cooled at −10° C. to−15° C. Thereto were gradually dropped triethylamine (20.98 g) andtrifluoromethanesulfonic acid trimethylsilyl ester (43.84 g) in theorder and the mixture was stirred at the same temperature for 1.5 hours.The reaction mixture was diluted with hexane, washed successively with asaturated aqueous sodium hydrogencarbonate solution and a saturatedaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to givetert-butyl trimethylsilyl(4-{1-[(trimethylsilyl)oxy]vinyl}phenyl)carbamate (36.4 g).

¹H NMR (400 MHz, CDCl₃) δ 0.17 (s, 9H), 60.24 (s, 9H),. 61.48 (s, 9H),4.38 (s, 1H), 4.86 (s, 1H), 6.98 (d, 2H, J=16 Hz), 7.52 (d, 2H, J=16Hz).

Step c)

To a solution of the compound (about 98.60 mmol) prepared in the aboveand(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (28.34 g) in dichloromethane (727 mL) was added at roomtemperature zinc iodide (9.44 g) and the mixture was stirred at the sametemperature for 4 hours. The reaction mixture was poured into ice water,diluted with ethyl acetate, extracted and separated. The organic layerwas washed successively with a saturated aqueous sodiumhydrogencarbonate solution and a saturated aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to give a crude product. The product waspurified by silica gel column chromatography to give tert-butyl4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamate (24.60 g).

¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 6H), 0.87 (s, 9H), 1.24 (d, 3H, J=6.0Hz), 2.87 (dd, 1H, J=2.4 Hz, 5.2 Hz), 3.11 (dd, 1H, J=10.0 Hz, 17.6 Hz),3.41 (dd, 1H, J=2.8 Hz, 17.2 Hz), 4.08–4.12 (m, 1H), 4.20–4.23 (m, 1H),6.11 (s, 1H), 6.71 (s, 1H), 7.47 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.0Hz).

Reference Example 31

Step a)

In the same manner as step a) of reference example 9, from tert-butyl4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamateprepared by step c) of reference example 30, there was obtained allyl[(2R,3S)-2-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}-2-oxoethyl)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(30.3 g).

LC/MS (EI) 822 (M+1)

Step b)

In the same manner as step b) of reference example 9, from the compound(3.0 g) prepared in the above step, there was obtained allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(2.53 g).

LC/MS (EI) 607 (M+1)

Reference Example 32

Allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(2.51 g) prepared by step b) of reference example 31 was dissolved inpyridine (50 mL) and the solution was cooled at 0° C. Thereto wasgradually dropped a solution of nicotinoyl chloride hydrochloride (0.85g) in pyridine (50 mL). The mixture was stirred at the same temperaturefor 10 minutes and then, diluted with ethyl acetate. The reactionmixture was poured into ice water, extracted with ethyl acetate andseparated. The organic layer was washed successively with a saturatedaqueous sodium hydrogencarbonate solution and a saturated aqueous sodiumchloride solution, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to give allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{4-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(3.32 g).

LC/MS (EI) 712 (M+1)

Reference Example 33

In the same manner as reference example 32 and at the reactiontemperature of 50° C. , from allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by step b) of reference example H2, there was obtained allyl((2R,3S)-3-[(1R)-1-hydroxyethyl]-2-{2-[4-(isonicotinoylylamino)phenyl]-2-oxoethyl}-4-oxoazetidin-1-yl)(triphenylphosphoranilidene)acetate.

LC/MS (EI) 712 (M+1)

Reference Example 34

In the same manner as reference example 32, from allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(2.50 g) prepared by step b) of reference example 31, there was obtainedallyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-{4-[(pyridin-2-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(2.69 g).

LC/MS (EI) 712 (M+1)

Reference Example 35

In the same manner as reference example 32, from allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by step b) of reference example 31, there was obtained allyl[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(2-{4-[(methoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 665 (M+1)

Reference Example 36

Step a)

In the same manner as step a) of reference example 30, from3-acetylphenyl isocyanate (25.00 g) and tert-butyl alcohol (38.75 g),there was obtained m-(N-tert-butoxycarbonyl)-aminoacetophenone (33.78g).

¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 2.60 (s, 3H), 6.58 (s, 1H), 7.38(t, 1H, J=8.0 Hz), 7.60–7.65 (m, 2H), 7.91 (s, 1H).

Step b)

In the same manner as step b) of reference example 30, fromm-(N-tert-butoxycarbonyl)aminoacetophenone (33.78 g) prepared in theabove step, there was obtained tert-butyltrimethylsilyl(3-{1-[(trimethylsilyl)oxy]vinyl}phenyl)carbamate (55.7g).

¹H NMR (400 MHz, CDCl₃) δ 0.17 (s, 9H), 60.24 (s, 9H), 81.48 (s, 9H),4.42 (s, 1H), 4.89 (s, 1H), 6.96 (d, 1H, J=8.0 Hz), 7.20 (s, 1H), 7.26(t, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz).

Step c)

In the same manner as step c) of reference example 30, from the compoundprepared in the above step, there was obtained tert-butyl3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamate (52.9 g).

¹H NMR (400 MHz, CDCl₃) δ 0.08 (s, 6H), 0.87 (s, 9H), 1.25 (d, 3H, J=6.4Hz), 2.89 (dd, 1H, J=2.4 Hz, 5.2 Hz), 3.16 (dd, 1H, J=10.4 Hz, 17.6 Hz),3.45 (dd, 1H, J=3.2 Hz, 18.0 Hz), 4.09–4.14 (m, 1H), 4.21–4.23 (m, 1H),6.10 (s, 1H), 6.60 (s, 1H), 7.40 (t, 1H, J=8.0 Hz), 7.60 (t, 2H, J=8.0Hz), 7.97 (s, 1H).

Reference Example 37

Step a)

In the same manner as step a) of reference example 9, from tert-butyl3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenylcarbamate (34.49 g) prepared by reference example 36, there was obtainedallyl[(2R,3S)-2-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}-2-oxoethyl)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(40.90 g).

LC/MS (EI) 822 (M+1)

Step b)

In the same manner as step b) of reference example 9, from the compound(10.0 g) prepared in the above step, there was obtained allyl{(2R,3S)-2-[2-(3-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(8.01 g).

LC/MS (EI) 607 (M+1)

Reference Example 38

In the same manner as reference example 32, from allyl{(2R,3S)-2-[2-(3-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by step b) of reference example 37, there was obtained allyl[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-(2-oxo-2-(3-[(pyridin-3-ylcarbonyl)amino]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate.

LC/MS (EI) 712 (M+1)

Reference Example 39

To a solution of(4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid (3.76 g) prepared by step b) of reference example 23 indichloromethane (40 ml) were added dimethylformamide (1 drop) andthionyl chloride (0.43 ml) and the mixture was stirred for 2 hours. Thereaction mixture was concentrated and dissolved in dichloromethane (40ml). Thereto were added triethylamine (3.43 ml), 4-dimethylaminopyridine(1.8 g) and 4-aminopyridine (0.93 g), and the mixture was stirred for 4hours. To the reaction mixture was added ethyl acetate and the mixturewas washed with an aqueous sodium hydrogencarbonate solution and asaturated aqueous sodium chloride solution. After the organic layer wasdried and concentrated, the residue was purified by silica gel columnchromatography (chloroform: methanol=30:1) to give allyl[(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-4-(2-oxo-2-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(1.0 g).

LC/MS (EI) 841 (M+1)

Reference Example 40

In the same manner as step d) of reference example 23 and step a) ofExample 2, from allyl[(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-4-(2-oxo-2-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}ethyl)azetidin-1-yl](triphenylphosphoranilidene)acetate(1.0 g) prepared by reference example 39, there was obtained allyl((3S,4R)-2-oxo-4-(2-oxo-2-{4-[2-oxo-2-(pyridin-4-ylamino)ethyl]phenyl}ethyl)-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(0.72 g).

Reference Example 41

To a solution of allyl{(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by step b) of reference example 31 in dimethylformamide wasadded imidazole and the solution was stirred for 12 hours. The reactionmixture was diluted with ethyl acetate, washed with a saturated aqueousammonium chloride solution and a saturated aqueous sodium chloridesolution. The organic layer was dried, concentrated and the residue waspurified by silica gel column chromatography (hexane: ethyl acetate=1:3)to give allyl[(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(2.13 g).

LC/MS (EI) 763 (M+1)

Reference Example 42

Step a)

To a solution of allyl[(2R,3S)-2-[2-(4-aminophenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(1.92 g) prepared by reference example 41 in tetrahydrofuran were addedtriethylamine (2.43 g) and ethyl isocyanate (0.84 g) and the mixture wasstirred at 50° C. for 30 hours. To the reaction mixture was added ethylacetate and the mixture was washed with an aqueous sodiumhydrogencarbonate solution and a saturated aqueous sodium chloridesolution. The organic layer was dried and concentrated to give allyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(4-{[(ethylamino)carbonyl]amino}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(2.06 g).

LC/MS (EI) 792 (M+1)

Step b)

In the same manner as step d) of reference example 23 and step a) ofexample 2, from allyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(4-{[(ethylamino)carbonyl]amino}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate,there was obtained allyl((2R,3S)-2-[2-(4-{[(ethylamino)carbonyl]amino}phenyl)-2-oxoethyl]-4-oxo-3-{((1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.

LC/MS (EI) 750 (M+1)

Reference Example 43

In the same manner as step b) of reference example 2, from allyl{(2R,3S)-2-[2-(3-aminophenyl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetateprepared by step b) of reference example 37, there was obtained allyl((2R,3S)-2-[2-(3-aminophenyl)-2-oxoethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate.

LC/MS (EI) 679 (M+1)

Reference Example 44

To a solution of allyl((2R,3S)-2-[2-(3-aminophenyl)-2-oxoethyl]-4-oxo3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(2.24 g) prepared by reference example 43 in dichloromethane, were added4-dimethylaminopyridine (2.04 g) and allyl chloroformate (1.06 g). Themixture was stirred for 2 hours. The reaction mixture was diluted withethyl acetate and washed with an aqueous sodium hydrogencarnonatesolution and a saturated aqueous sodium chloride solution. The organiclayer was dried, concentrated and the residue was purified with silicagel column chromatography (hexane: ethyl acetate=1:3) to give allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}phenyl)-2-oxoethyl]-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(1.65 g).

LC/MS (EI) 763 (M+1)

INDUSTRIAL APPLICABILITY

By the present invention, it becomes possible to provide a β-lactamantibiotic with a high oral absorbability showing an excellentantibacterial activity over a broad range of Gram-positive andGram-negative bacteria, in particular, penicillin-resistantStreptococcus pneumoniae (PRSP) which has been isolated at an elevatedfrequency in recent years and thus causes a serious clinical problem,and Haemophilus influenzae which has acquired resistance against theexisting β-lactam antibiotics over a wide scope due topenicillin-binding protein (PBP) mutations such as β-lactamasenon-producing ampicillin-registant (BLNAR) Haemophilus influenzae.

1. A carbapenem compound represented by the formula [1]:

wherein ring E is benzene or thiophene; R¹ is C₁ to C₃ alkyl or C₁ to C₃ alkyl substituted by hydroxy; A is —CH₂—O— and R⁰ is the formula [2]:

wherein X is oxygen atom, R² is (1) hydrogen atom, (2) C₁ to C₆ alkyl, (3) C₃ to C₇ cycloalkyl, (4) aryl which may optionally contain heteroatom(s) therein, (5) aralkyl in which ring may optionally contain heteroatom(s), or (6) 3 to 7 membered hetero ring, R³ is (2) C₁ to C₆ alkyl, (3) C₃ to C₇ cycloalkyl, (4) aryl which may optionally contain heteroatom(s) therein, (5) aralkyl in which ring may optionally contain heteroatom(s), or (6) 3 to 7 membered hetero ring; or R² and R³ are combined together with the N atom to form a 3 to 7 membered hetero ring, or A is —CH₂—NH— and R⁰ is the formula [3]:

wherein X is oxygen atom, m is 1, R^(3a) is C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, aryl which may optionally contain heteroatom(s) therein, aralkyl in which ring may optionally contain heteroatom(s), or 3 to 7 membered hetero ring; R is hydrogen atom, C₁ to C₆ alkyl, C₂ to C₁₂ alkyloxyalkyl, (2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxol-4-yl)rnethyl, or the formula [4]:

wherein R⁶ is hydrogen atom or C₁ to C₆ alkyl, R⁷ is C₁ to C₆ alkyl, or C₃ to C₇ cycloalkyl and n is 0 or 1, and Y is hydrogen atom, or its pharmaceutically acceptable salt.
 2. A carbapenem compound represented by the formula [1d]:

wherein ring E is benzene or thiophene; A is —CH₂—O— and R⁰ the formula [2]:

wherein X is oxygen atom, R² is (1) hydrogen atom, (2) C₁ to C₆ alkyl, (3) C₃ to C₇ cycloalkyl, (4) aryl which may optionally contain heteroatom(s) therein, (5) aralkyl in which ring may optionally contain heteroatom(s), or (6) 3 to 7 membered hetero ring, R³ is (2) C₁ to C₆ alkyl, (3) C₃ to C₇ cycloalkyl, (4) aryl which may optionally contain heteroatom(s) therein, (5) aralkyl in which ring may optionally contain heteroatom(s), or (6) 3 to 7 membered hetero ring; or R² and R³ are combined together with the N atom to form a 3 to 7 membered hetero ring, or A is —CH₂—NH— and R⁰ is the formula [3]:

wherein X is oxygen atom, m is 1, R^(3a) is C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, aryl which may optionally contain heteroatom(s) therein, aralkyl in which ring may optionally contain heteroatom(s), or 3 to 7 membered hetero ring; R is hydrogen atom, C₁ to C₆ alkyl, C₂ to C₁₂ alkyloxyalkyl, (2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl, or the formula [4]:

wherein R⁶ is hydrogen atom or C₁ to C₆ alkyl, R⁷ is C₁ to C₆ alkyl or C₃ to C₇ cycloalkyl, and n is 0 or 1; Y is hydrogen atom, or its pharmaceutically acceptable salt.
 3. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, A is —CH₂O— and R⁰ is the formula [2a]:

wherein R² is hydrogen atom or C₁ to C₆ alkyl, and R³ is C₁ to C₆ alkyl, or A is —CH₂NH— and R⁰ is the formula [3a]:

wherein m is 1, and R^(3a) is C₁ to C₆ alkyl.
 4. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, A is —CH₂O— and R⁰ is the formula [2a]:

wherein R² is hydrogen atom or C₁ to C₆ alkyl and R³ is C₁ to C₆ alkyl, or A is —CH₂NH— and R⁰ is the formula [3a]:

wherein m is 1, and R^(3a) is C₁ to C₆ alkyl, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or the formula [4]:

wherein R⁶, R⁷ and n are the same as defined in claim
 2. 5. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, A is —CH₂O— and R⁰ is the formula [2a]:

wherein R² is hydrogen atom and R³ is C₁ to C₆ alkyl, or A is —CH₂NH— and R⁰ is the formula [3a]:

wherein m is 1, and R^(3a) is C₁ to C₆ alkyl, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or the formula [4]:

wherein R⁶, R⁷ and n are the same as defined in claim 2, and wherein the A is bound to the benzene ring at a meta or para position with respect to the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene ring.
 6. A pharmaceutical composition comprising the carbapenem compound or its pharmaceutically acceptable salt according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier, excipient, binder or stabilizer.
 7. A pharmaceutical composition comprising the carbapenem compound or its pharmaceutically acceptable salt according to claim 2 as an active ingredient together with a pharmaceutically acceptable carrier, excipient, binder or stabilizer.
 8. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl; A is —CH₂O— and R⁰ is CONHCH₃.
 9. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl; A is —CH₂NH— and R⁰ is COOCH₃.
 10. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl; A is —CH₂O— and R⁰ is CONHCH₃, and wherein the A is bound to the benzene ring at a meta or para position with respect to the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene ring.
 11. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl; A is —CH₂NH— and R⁰ is COOCH₃, and wherein the A is bound to the benzene ring at a meta or para position with respect to the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene ring.
 12. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl, A is —CH₂O— and R⁰ is CONHCH₃ and wherein the A is bound to the benzene ring at a para position with respect to the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene ring.
 13. The carbapenem compound or its pharmaceutically acceptable salt according to claim 2, wherein ring E is benzene, R is hydrogen atom, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, or pivaloyloxymethyl, A is —CH₂NH— and R⁰ is COOCH₃, and wherein the A is bound to the benzene ring at a para position with respect to the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is bound to the benzene ring. 